WO2020233641A1 - Compound used as ret kinase inhibitor and application thereof - Google Patents

Compound used as ret kinase inhibitor and application thereof Download PDF

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Publication number
WO2020233641A1
WO2020233641A1 PCT/CN2020/091425 CN2020091425W WO2020233641A1 WO 2020233641 A1 WO2020233641 A1 WO 2020233641A1 CN 2020091425 W CN2020091425 W CN 2020091425W WO 2020233641 A1 WO2020233641 A1 WO 2020233641A1
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ring
alkyl
group
alkoxy
cycloalkyl
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PCT/CN2020/091425
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French (fr)
Chinese (zh)
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李钧
郑茂林
牛成山
梁阿朋
吴豫生
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浙江同源康医药股份有限公司
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Priority to JP2021569540A priority Critical patent/JP2022534067A/en
Priority to EP20810190.7A priority patent/EP3974422A4/en
Priority to AU2020280699A priority patent/AU2020280699B2/en
Priority to US17/613,311 priority patent/US20220233513A1/en
Priority to CN202080032938.5A priority patent/CN113784963B/en
Publication of WO2020233641A1 publication Critical patent/WO2020233641A1/en

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology, in particular to compounds used as RET kinase inhibitors, and their application in regulating RET kinase activity or treating RET-related diseases.
  • the RET (Rearranged during transfection, rearrangement during transfection) gene is located on chromosome 10.
  • the RET protein it encodes is a receptor tyrosine kinase (RTK) that exists on the cell membrane.
  • RTK receptor tyrosine kinase
  • Its mutation types mainly include KIF5B, Fusion mutations in genes such as TRIM33, CCDC6 and NCOA4, and point mutations in M918T.
  • Common RET mutations mainly occur in many types of cancers such as thyroid cancer and non-small cell lung cancer.
  • the incidence of RET gene fusion in NSCLC patients is about 1% to 2%, and the incidence in papillary thyroid cancer (accounting for about 85% of all thyroid cancers) is 10% to 20%.
  • RET fusion occurs in young patients.
  • the current treatment plan for RET gene modification is mainly to use multi-kinase inhibitor drugs, such as cabozantinib and vandetanib. Due to the low targeting, severe toxicity related to VEGFR inhibition usually occurs due to off-target.
  • Blueprint and Loxo Oncology announced their development of efficient and selective oral RET inhibitors BLU-667 and LOXO-292.
  • Blueprint Phase I clinical data showed that BLU-667 exhibits extensive anti-tumor activity.
  • the overall response rate (ORR) in tumor patients with RET fusion and mutation is 45%.
  • patients with non-small cell lung cancer and medullary thyroid cancer ORR is 50% and 40%, respectively.
  • Loxo Oncology's research drug LOXO-292 breakthrough therapy designation for the treatment of non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC) patients with RET gene mutations.
  • NSCLC non-small cell lung cancer
  • MTC medullary thyroid cancer
  • the present invention provides a new compound with RET kinase inhibitory activity and better pharmacodynamics and pharmacokinetic properties.
  • the first aspect of the present invention provides a compound for use as a RET kinase inhibitor, the compound being a compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
  • R 1 is a substituted or unsubstituted 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the substitution refers to optionally substituted by one or more R 2 ;
  • X 3 is selected from: O, NR 8 , CR 9 R 10 ,
  • R 8 and R 11 are each independently selected from: hydrogen, C1 ⁇ C6 alkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 heteroalkyl, C3 ⁇ C6 ring Alkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, aralkyl, C3-C6 heterocycloalkyl;
  • R 9 and R 10 are each independently selected from: hydrogen, halogen, C1-C6 alkane Group, C1 ⁇ C6 haloalkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C3 ⁇ C6 cycloalkyl, C3 ⁇ C6 halocycloalkyl, Aryl, heteroaryl,
  • Ring W is a substituted or unsubstituted heterocyclylene or heteroarylene, and the substitution means optionally substituted with 0-2 R 5 ;
  • Ring Q1 is optionally selected from: 3 to 7-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged rings, and may contain 0 to 3 heteroatoms, and heteroatoms are optionally selected from N, O, S; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl;
  • X 5 is selected from: C(O), S(O), S(O) 2 ,
  • X 6 is selected from: CR 9 , N, O;
  • R 2 is optionally selected from: hydrogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C1 ⁇ C6 heteroalkyl, each of which is alkyl, alkoxy Group, alkylamino group, cycloalkyl group and heteroalkyl group are optionally and independently substituted with 0-5 Ra ;
  • A is optionally selected from: 3 to 7-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged rings, and may contain 0 to 3 heteroatoms, and heteroatoms are optionally selected from N, O, S ;
  • Any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 Thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl;
  • R 3 is optionally selected from: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each alkyl group, Alkoxy, alkylamino, cycloalkyl and heteroalkyl are optionally and independently substituted with 0-5 Ra ;
  • R 4 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1 ⁇ C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1 ⁇ C6 alkylene)-S(O) 2 R 6 , -(C1 ⁇ C6 alkylene)-S(O) 2 -N(R 6 )
  • R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, oxo, cyano, -C(O)R 6 , -OC (O)R 6 , -C(O)OR 6 , -(C1 ⁇ C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1 ⁇ C6 alkylene)-S(O) 2 R 6 , -(C1 ⁇ C6 alkylene)-S(O) 2 -N
  • R 6 and R 7 are each independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkane Group, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
  • R a optionally from: C1 ⁇ C6 alkyl, halogen, hydroxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy group, C1 ⁇ C6 alkyl group, a cycloalkyl group, a heterocyclic group, or a cyano group;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0 or 1
  • the limiting condition is: when ring W is a substituted or unsubstituted 6-membered heteroaryl group, ring W is substituted by X 4 , wherein X 4 is selected from: CN,
  • ring W is a substituted or unsubstituted group of the following groups: 5-6 membered monocyclic heterocyclylene, 8-10 membered bicyclic heterocyclylene or 5-6 membered monocyclic heteroarylene Group or 8-10 membered bicyclic heteroarylene; the substitution refers to optionally substituted with 0-2 R 5 ;
  • R 5 is each independently optionally selected from: hydrogen, C1-C6 alkyl, C2-C6 alkene Group, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, Heterocyclyl, heterocycloalkyl, nitro, oxo, cyano, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1
  • the W ring is selected from: Wherein, X 1 , X 2 , X 7 , and X 8 are each independently selected from N or CR 5 ; and at least one of X 7 and X 8 is N;
  • R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl group, nitro group, cyano group, amino group; wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group and cycloalkyl group are each independently covered by 0-5 R a substituent; R & lt optionally a from: C1 ⁇ C6 alkyl, halogen, hydroxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy group, C1 ⁇ C6 alkyl group, a cycloalkyl group, heterocycloalkyl or cyano Group; Ring Q2 is optional from: five-membered, six-membered
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has formula (II), formula (III) or formula (IV) ) Shows the structure,
  • A is optionally selected from a saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring of 3 to 7 members, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S;
  • Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 Thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl; in the formula In (II), Q1 is connected to ring B only through the carbon atom on ring Q1;
  • R 1 is optionally selected from one of the following structures:
  • R 2 is optionally selected from hydrogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, C3 ⁇ C6 cycloalkyl, C1 ⁇ C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl
  • the group is optionally and independently substituted with 0-5 Ra ;
  • R 3 is optionally selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each of alkyl, alkoxy, cycloalkyl and Heteroalkyl is optionally and independently substituted with 0-5 Ra ;
  • R a is optionally selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano;
  • X 1 and X 2 are each independently selected from N or CR 5 ;
  • X 3 is selected from O, NR 8 , CR 9 R 10 ,
  • R 8 and R 11 are each independently selected from hydrogen, C1 ⁇ C6 alkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 heteroalkyl, C3 ⁇ C6 cycloalkyl , C3-C6 halocycloalkyl, aryl, heteroaryl, aralkyl, C3-C6 heterocycloalkyl;
  • R 9 and R 10 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1 ⁇ C6 haloalkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C3 ⁇ C6 cycloalkyl, C3 ⁇ C6 halocycloalkyl, aryl, Heteroaryl
  • X 4 is selected from CN
  • X 5 is selected from C(O), S(O), S(O) 2 ,
  • X 6 is selected from CR 9 , N, O;
  • R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 heteroalkyl, cycloalkyl , Aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C( O)OR 6 , -(C1 ⁇ C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1 ⁇ C6 alkylene)-S(O) 2 R 6 , -(C1 ⁇ C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ), -N(
  • Ring Q2 is optionally selected from a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N , O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl , C1 ⁇ C6 thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl base;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0 or 1.
  • X 3 is NR 8 , wherein R 8 is H.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has formula (2), formula (3) or formula (4) ) Shows the structure,
  • A is optionally selected from a saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring of 3 to 7 members, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S;
  • Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 Thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl; in the formula In (2), Q1 is connected to ring B only through the carbon atom on ring Q1;
  • R 1 is optionally selected from one of the following structures:
  • R 2 is optionally selected from hydrogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, C3 ⁇ C6 cycloalkyl, C1 ⁇ C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl
  • the group is optionally and independently substituted with 0-5 Ra ;
  • R 3 is optionally selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each of alkyl, alkoxy, cycloalkyl and Heteroalkyl is optionally and independently substituted with 0-5 Ra ;
  • R a is optionally selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano;
  • X 1 and X 2 are each independently selected from N or CR 5 ;
  • R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 heteroalkyl, cycloalkyl , Aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C( O)OR 6 , -(C1 ⁇ C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1 ⁇ C6 alkylene)-S(O) 2 R 6 , -(C1 ⁇ C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ), -N(
  • Ring Q2 is optionally selected from a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N , O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl , C1 ⁇ C6 thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl base;
  • n 0, 1, 2, 3, 4, 5 or 6.
  • the W ring of the compound of formula I' is selected from the following group:
  • R 12 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, amino;
  • Each Y 1 , Y2 and Y3 is independently selected from: O, N, NR 17 , CR 13 , CR 13 R 14
  • R 17 is selected from: H, C1-C6 alkyl.
  • the W ring is selected from:
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2'
  • Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
  • f 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , A and m are as described above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2"
  • R 1 , R 2 , R 3 , R 4 , A, m, X 1 , X 2 and R 17 are as described above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3'
  • Y 4 is selected from: N or CR 17 ,
  • Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
  • f 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • p 0, 1, 2, 3;
  • X 2 , Q2, R 1 , R 2 , R 3 , R 4 , A and m are defined as described above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3"
  • R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
  • Y 1 , Y 2 , Y 3 , R 12 , R 13 , R 14 , R 15 and R 16 are as described above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 4'
  • Y 4 is selected from: N or CR 17 ;
  • Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
  • f 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • p 0, 1, 2, 3;
  • X 2 , Q2, R 1 , R 2 , R 3 , R 4 , A and m are defined as described above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4"
  • R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5 and formula 6:
  • R 1 , X 7 , X 8 , X 2 , Q2, R 2 , R 3 , R 4 , R 17 , A and m are as defined above, and at least one of X 7 and X 8 is N.
  • A is an aromatic ring, a heteroaromatic ring, and the heteroaromatic ring contains 0 to 3 heteroatoms, heteroatoms can be selected from N, O, S; any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, Amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl.
  • A is phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, and any hydrogen atom on ring A can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester Group, amide group, ketone carbonyl group, amino group, C1 ⁇ C6 alkyl group, C1 ⁇ C6 haloalkyl group, C1 ⁇ C6 thioalkyl group, C1 ⁇ C6 alkoxy group, C1 ⁇ C6 heteroalkyl group, C1 ⁇ C6 alkylamino group , C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or heteroaryl.
  • R 4 is each independently selected from: aryl, heteroaryl , an aryloxy group, an aralkyl group, a heterocyclic group; wherein each aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl independently substituted with 0 to 5 R a; R a to any Selected from: C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
  • R 4 is 5-membered heteroaryl group, the heteroaryl group may be independently substituted with 0 to 5 R a; R a optionally from: C1 ⁇ C6 alkyl group, halo, hydroxy , C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
  • R 4 is selected from: Wherein, R 18 is selected from: halogen (preferably F), C1-C6 alkyl.
  • n 1
  • R 3 is H, C1-C6 alkyl, C1-C6 alkoxy.
  • R 2 is H.
  • R 1 , X 3 , W, Q1, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are specific groups corresponding to the specific compounds in the embodiments .
  • R 1 , X 1 , X 2 , X 3 , Q1, Q2, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are specific compounds in the embodiment The corresponding specific group.
  • X 9 and X 10 are each independently selected from N or CR 5 , wherein each of R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, C1 ⁇ C6 alkylamino, halogen, C1 ⁇ C6 heteroalkyl, cycloalkyl, nitro, cyano, amino; wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkane amino, heteroalkyl, cycloalkyl independently substituted with 0 to 5 R a; R a optionally from: C1 ⁇ C6 alkyl, halogen, hydroxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy Group, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula 5'or 6'
  • X 2 , X 7 , X 8 , X 9 , and X 10 are each independently selected from: N or CR 5 , and at least one of X 7 and X 8 is N,
  • R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl group, nitro group, cyano group, amino group; wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group and cycloalkyl group are each independently covered by 0-5 R a substituent; R & lt optionally a from: C1 ⁇ C6 alkyl, halogen, hydroxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy group, C1 ⁇ C6 alkyl group, a cycloalkyl group, heterocycloalkyl or cyano base;
  • Ring Q2 is optionally selected from: a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkane Group, C1 ⁇ C6 thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 cycloalkylamino, aryl or hetero Aryl.
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof can be selected from the compound represented by the following structure:
  • the compound is selected from the compounds shown in the examples.
  • the inorganic acid salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate;
  • the organic acid salt is selected from formate, ethyl Acid salt, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, Citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
  • a pharmaceutical composition containing a therapeutically effective amount of the compound of formula I'described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, And a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may also contain one or more other therapeutic agents, and the other therapeutic agents are selected from: PD-1 inhibitors (such as nivolumab, pembrolizumab) , JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 Inhibitors (such as Devaluzumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs Etc.), CD20 antibodies (such as rituximab, obin eutuzumab, ofatumumab, tositumomab, ibritum
  • Pabocinil, Ribocinil, Abemaciclib, Lerociclib, etc. MEK inhibitors (e.g. Smeltinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC- 4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.) or combinations thereof.
  • MEK inhibitors e.g. Smeltinib (AZD6244), Trametin
  • a compound of formula I'as described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof for the preparation of a RET kinase inhibitor drug Applications.
  • a compound of formula I'as described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in preparation for regulating RET kinase activity or Application of drugs to treat RET-related diseases.
  • the RET-related diseases include cancer.
  • the cancer is thyroid cancer or lung cancer.
  • the cancer is medullary thyroid carcinoma or non-small cell lung cancer.
  • the inventors unexpectedly discovered a class of compounds with better RET kinase inhibitory activity.
  • the compound has excellent inhibitory activity on RET kinase, and has better pharmacodynamic/pharmacokinetic properties.
  • the present invention has been completed.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • Alkyl refers to a monovalent linear or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms and containing 1 to 12 carbon atoms.
  • the alkyl group is preferably a C1-C6 alkyl group (ie, contains 1, 2, 3, 4, 5, or 6 carbon atoms).
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl and the like.
  • an alkyl group is also intended to include a substituted alkyl group, that is, one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Haloalkyl refers to an alkyl group as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyl groups include -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl (for example, -CF 3 ), and the like.
  • Alkylene refers to a divalent group of an alkyl group, such as -CH 2 -, -CH 2 CH 2 -and -CH 2 CH 2 CH 2 -.
  • Alkoxy refers to an alkyl group to which an oxy group is attached, which has an alkyl O- structure, wherein the alkyl group has the definition as described above.
  • the alkoxy group The group is a C1-C6 alkoxy group.
  • Alkoxy includes but is not limited to methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • Haloalkoxy refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Thioalkyl means that the carbon in the alkyl group is replaced by S, S(O) or S(O)2.
  • alkenyl refers to an aliphatic group containing at least one double bond, usually having 2 to 20 carbon atoms.
  • C2-C6 alkenyl refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms.
  • Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.
  • alkenyl includes substituted alkenyl.
  • Alkenylene refers to an alkenyl group having two points of attachment.
  • the alkenylene group may also be in an unsubstituted form or a substituted form with one or more substituents.
  • Alkynyl refers to a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by one or more triple bonds, usually having 2 to 20 carbon atoms .
  • C2-6 alkynyl refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
  • alkynyl groups also include substituted alkynyl groups.
  • Alkynylene refers to an alkynyl group having two points of attachment.
  • ethynylene means the group: -C ⁇ C-.
  • the alkynylene group may also be in an unsubstituted form or a substituted form with one or more substituents.
  • Aliphatic group refers to a straight chain, branched chain or cyclic hydrocarbon group, including saturated and unsaturated groups such as alkyl, alkenyl and alkynyl groups.
  • Aromatic ring system refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.
  • Aryl refers to a monovalent group of an aromatic ring system.
  • Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl; and ring systems in which an aromatic carbocyclic ring is fused with one or more non-aromatic carbocyclic rings, such as indanyl and phthalyl Carboximide group, naphthyl imino group or tetrahydronaphthyl group and so on.
  • the aryl group is preferably a C6-C12 aryl group.
  • the aryl group is also intended to include substituted aryl groups.
  • Arylalkyl or “aralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
  • the aralkyl group includes a group in which one or more hydrogen atoms are replaced by an aryl group, and the aryl group and the alkyl group have the definitions described above.
  • Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, trityl and the like.
  • Aryloxy refers to -O-(aryl), where the aryl moiety is as defined herein.
  • Heteroalkyl refers to a substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Numerical ranges can be given, for example, C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, the -CH 2 OCH 2 CH 3 group is referred to as a "C3" heteroalkyl. The connection to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl chain.
  • Heteroalkylene refers to an optionally substituted divalent alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof.
  • Carbocyclic ring system refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, in which each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic.
  • Carbocyclyl refers to a monovalent group of a carbocyclic ring system. Examples include cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (for example, cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).
  • Cycloalkyl refers to a monovalent saturated carbocyclic group composed of a mono- or bicyclic ring, which has 3-12, preferably 3-10, more preferably 3-6 ring atoms. Cycloalkyl groups may be optionally substituted with one or more substituents, where each substituent is independently a hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Cycloalkoxy refers to a group of formula -OR, where R is a cycloalkyl as defined herein.
  • Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cycloalkylalkyl refers to -(cycloalkyl)-alkyl in which cycloalkyl and alkyl are as disclosed herein.
  • Cycloalkylalkyl is bonded to the parent molecular structure through a cycloalkyl group.
  • Heteroaromatic ring system refers to a single ring (e.g. 5 or 6 membered), bicyclic (6-12 membered) or polycyclic ring system, in which at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O or S); and none of the other rings are heterocyclic groups (as defined below).
  • rings that are aromatic and contain heteroatoms contain 1, 2, 3, or 4 ring heteroatoms in the ring.
  • At least one ring is heteroaromatic, and the remaining rings can be saturated, partially unsaturated or fully unsaturated.
  • Heteroaryl refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (e.g., 8-10 membered) or tricyclic group of 5 to 12 ring atoms, which contains at least one group consisting of 1, 2, or The 3 ring heteroatoms selected from N, O or S, and the remaining ring atoms are the aromatic ring of C. It should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring.
  • heteroaryl groups include, but are not limited to: imidazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, Benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo Azolyl, benzo Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazoline Group, quinazinyl, naphthyridinyl, pterridinyl
  • Heterocyclic ring system refers to monocyclic, bicyclic and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and the ring contains at least one heteroatom.
  • the heterocyclic ring system can be attached to any heteroatom or pendant group at a carbon atom, which results in a stable structure and any ring atom can be optionally substituted.
  • Heterocyclic group refers to a monovalent group of a heterocyclic ring system, usually refers to a stable monocyclic ring (such as 3-8 members, that is, 3, 4, 5, 6, 7 or 8 members) or two Ring (such as 5-12 yuan, that is 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered) or multi-membered ring (such as 7-14 yuan, that is 7-membered, 8-membered , 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14), including fused ring, spiro ring and/or bridged ring structure, which are saturated, partially unsaturated, and contain carbon atoms and 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S.
  • heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, Pyrrolidone, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepinyl, oxazepinyl, thiol Azepinyl, morpholinyl and quinuclidinyl; (2) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetra Hydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-
  • Heterocyclylene refers to a heterocyclic group having two attachment sites.
  • the heterocyclylene is a bicyclic ring, one of which is a heteroaryl group, and is connected to the other part of the general formula through the heteroaryl group.
  • the heterocyclylene is preferably a 5-6 membered monocyclic heterocyclylene or an 8-10 membered bicyclic heterocyclylene.
  • Heterocyclylalkyl refers to an alkyl group substituted with a heterocyclic group, wherein the definitions of the heterocyclic group and the alkyl group are as described above.
  • Alkylamino refers to a group having an alkyl-NR- structure, wherein R is H, or an alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc. as described above.
  • Cycloalkylamino refers to a group of formula -NRaRb, wherein Ra is H, alkyl as defined herein, or cycloalkyl as defined herein, Rb is cycloalkyl as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrolyl.
  • a C3-C8 cycloalkylamino group refers to an amino group containing 3-8 carbon atoms.
  • ester group refers to a structure -C(O)-OR or RC(O)-O-, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , Heterocyclic group, as defined above.
  • amide group refers to a group with the structure -CONRR', wherein R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkane Group, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R'may be the same or different in the dialkylamine segment.
  • sulfonamide group refers to a group with the structure -SO 2 NRR', wherein R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to Alkyleneoxy and so on.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 ureido and so on.
  • Cyano refers to the -CN group.
  • Niro refers to -NO 2 .
  • Halogen (halo) refers to any halogen group, for example, -F, -Cl, -Br, or -I.
  • Deuterated compound refers to a compound obtained by replacing one hydrogen atom (H) or multiple hydrogen atoms (H) with deuterium atoms (D) in a compound.
  • the term "plurality” means 2, 3, 4, 5 independently.
  • the terms "compounds of the present invention” or “active ingredients of the present invention” are used interchangeably and refer to compounds of formula I', or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds (such as deuterium Substitute compound) or prodrug.
  • the term also includes racemates and optical isomers.
  • R 1 , X 3 , W, Q1, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are as described above, and the ring W is preferably a substituted or unsubstituted group :5-6 membered monocyclic heterocyclylene, 8-10 membered bicyclic heterocyclylene or 5-6 membered monocyclic heteroarylene or 8-10 membered bicyclic heteroarylene; said substitution means optional Ground is substituted by 0-2 R 5 ; R 5 is each independently selected from: hydrogen, C1 ⁇ C6 alkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 alkane Amino, halogen, C1-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclic, heterocycloalkyl, nitro,
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula (II), formula (III) or formula (IV)
  • R 1 , X 1 , X 2 , X 3 , Q1, Q2, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are as defined above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula (2), formula (3) or formula (4)
  • R 1 , X 1 , X 2 , Q1, Q2, R 2 , R 3 , R 4 , A and m are as defined above.
  • the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has the structure shown in formula 2'
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , A, R 17 , f, and m are defined as described above.
  • the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has the structure shown in formula 2"
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , A, m and R 17 are as defined above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3'
  • Y 4 is selected from: N or CR 17 ,
  • R 1 , X 2 , R 2 , R 3 , R 4 , R 17 , A, m, f, p, and Q2 are as defined above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3"
  • R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4':
  • Y 4 is selected from: N or CR 17 ;
  • R 1 , X 2 , R 2 , R 3 , R 4 , R 17 , A, m, f, p, and Q2 are as defined above.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4",
  • R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
  • the compound of Formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in Formula 5 and Formula 6:
  • R 1 , X 7 , X 8 , X 2 , Q2, R 2 , R 3 , R 4 , R 17 , A and m are as defined above, and at least one of X 7 and X 8 is N.
  • R 1 is optionally selected from one of the following structures:
  • R 1 is
  • R 2 is optionally selected from hydrogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, C3 ⁇ C6 cycloalkyl, C1 ⁇ C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl
  • the group is optionally and independently substituted with 0-5 Ra ;
  • R a optionally from C1 ⁇ C6 alkyl, halogen, hydroxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano.
  • the W ring is selected from: among them,
  • R 12 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, amino;
  • Each of Y 1, Y 2, Y 3 is independently selected from: O, N, NR 17 , CR 13 , CR 13 R 14 ;
  • R 17 is selected from: H, C1-C6 alkyl.
  • A is an aromatic ring or a heteroaromatic ring. More preferably, A is a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a pyridazinyl group; the heteroaromatic ring contains 0 to 3 Heteroatoms, heteroatoms can be selected from N, O, S; any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkyl, C1 ⁇ C6 thioalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkylamino, C3 ⁇ C6 cycloalkyl, C3 ⁇ C8 ring Alkylamino, aryl
  • R 4 is independently selected from: aryl, heteroaryl, aryloxy, aralkyl, heterocyclic group, more preferably R 4 is a 5-membered heteroaryl group; wherein, each aryl, heteroaryl, aryloxy, arylalkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0 to 5 R a; R a optionally from: C1 ⁇ C6 alkyl group, halo , Hydroxyl, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano; more preferably R 4 is selected from: Wherein, R 18 is selected from: halogen (preferably F), C1-C6 alkyl.
  • m is 1.
  • R 3 is H, C1-C6 alkyl, or C1-C6 alkoxy.
  • R 2 is H.
  • X 9 and X 10 are each independently selected from N or CR 5 , wherein each of R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, C1 ⁇ C6 alkylamino, halogen, C1 ⁇ C6 heteroalkyl, cycloalkyl, nitro, cyano, amino; wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkane amino, heteroalkyl, cycloalkyl independently substituted with 0 to 5 R a; R a optionally from: C1 ⁇ C6 alkyl, halogen, hydroxy, C1 ⁇ C6 heteroalkyl, C1 ⁇ C6 alkoxy Group, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
  • the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5'or 6'
  • X 2 , X 7 , X 8 , X 9 , X 10 and Q2 ring are as described above, and at least one of X 7 and X 8 is N.
  • salts that the compounds of the present invention may form also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt in the acid or basic form formed with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion (“internal salt”) that may be formed is contained in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate.
  • Benzene sulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed by organic bases (such as organic amines), such as benzathine and dicyclohexylamine , Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfate (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • small molecular alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide
  • dialkyl sulfate E.g., dimethyl sulfate, diethyl,
  • prodrugs and solvates of the compounds of the present invention are also covered.
  • prodrug herein refers to a compound that undergoes metabolism or chemical transformation through a chemical process to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • the compounds of the present invention include solvates such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin the mixture and other mixtures.
  • the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the mixture of isomers can contain various isomer ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those skilled in the art and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in fact, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotope-labeled compounds in the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by a general method, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant.
  • the pure enantiomer if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their coverage.
  • the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • each reaction is usually carried out at 0 to 90° C. under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.
  • the preferred preparation method is as follows:
  • alkaline such as potassium carbonate, sodium carbonate, etc.
  • catalyst and ligand such as Pd(PPh 3 ) 4
  • alkaline such as diisopropylethylamine, potassium acetate, DBU, etc.
  • a catalyst and Body such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 ⁇ t-BuXphos, etc.
  • the third step in the presence of an inert solvent (such as DMF) and a condensing agent (such as DMAP, HATU, PyBOP, etc.), versus Reaction to obtain formula I'.
  • an inert solvent such as DMF
  • a condensing agent such as DMAP, HATU, PyBOP, etc.
  • alkaline such as diisopropylethylamine, potassium acetate, DBU, etc.
  • a catalyst and Body such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 ⁇ t-BuXphos, etc.
  • Step 2 In an inert solvent (such as DMF/H 2 O), under alkaline (such as K 2 CO 3 ) conditions, in the presence of catalysts and ligands (such as Pd(PPh 3 ) 4 ), Response, get
  • G and G' are each independently a halogen (such as F, Cl, Br);
  • G" is a borate group (such as );
  • X 3 ' is selected from: OH, -NHR 8 , -CHR 9 R 10 ,
  • X 5 ' is selected from: -C(O)-OH, -S(O)-OH, -S(O) 2 -OH,
  • R 1 , X 3 , W, Q1, X 5 , X 6 , R 2 , R 3 , R 4 , A, Q2, m and n are as described above.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the compound of formula I' can be combined with other drugs known to treat or improve similar conditions.
  • the original drug administration mode and dosage can remain unchanged, while the compound of formula I'is administered simultaneously or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula I'can be preferably used.
  • the combination of drugs also includes taking the compound of formula I'and one or more other known drugs in overlapping time periods.
  • the dose of the compound of formula I'or the known drug may be lower than the dose of the compound used alone.
  • the drugs or active ingredients that can be used in combination with the compound of formula I'in include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB -A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biological analogues of the above drugs, etc.), PD-L1 inhibitors (such as devaluzumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituo Coximab, obin utuzumab, ofatumumab, tositumomab, ibimuma
  • Pabocinib Reboscine, Abemaciclib, Lerociclib, etc.
  • MEK inhibitors e.g. Simetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI -1040) etc.
  • Akt inhibitors such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.
  • mTOR inhibitors such as Vistusertib, etc.
  • SHP2 inhibitors such as RMC-4630, JAB-3068, TNO155, etc.
  • IGF-1R inhibitors such as Ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano formulation.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and gly
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, which comprises the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula I'or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention The compound is mixed to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of: administering the compound of formula I'in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, to a subject in need of treatment, or Administration of the pharmaceutical composition of the present invention is used to inhibit RET.
  • the compound of the present invention has excellent inhibitory ability on RET kinase
  • the compound of the present invention has lower toxic and side effects
  • the compound of the present invention has better pharmacodynamics and pharmacokinetic properties.
  • the experiment process is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Phase A water (containing 0.1% trifluoroacetic acid)
  • Phase A water (containing 0.1% trifluoroacetic acid)
  • reaction solution was poured into water (20mL) and extracted with ethyl acetate for 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, column chromatography to obtain the crude product and then prepared and separated to obtain C32 (123mg, purity: 95.7%), [M+H]: 542.3.
  • the biological activity test experiment process is as follows:
  • Each sample was prepared into a solution with a concentration of 10 mM.
  • test compound is dissolved to a specific concentration in 100% dimethyl sulfoxide.
  • the kinase activity data is expressed as the percentage of kinase activity remaining in the test sample compared to the vehicle (dimethyl sulfoxide) reaction.
  • Prism GRAPHPAD software was used to obtain IC50 values and curve fitting.
  • Table 1 shows the IC50 (nM) value of the obtained test sample's inhibitory activity against wild-type RET.
  • RPMI-1640 was purchased from BI.
  • Fetal bovine serum was purchased from BI.
  • DMSO dimethyl sulfoxide
  • BaF3 cells were purchased from RIKEN BRC CELL BANK.
  • Ba/F3-KIF5B-RET, Ba/F3-KIF5B-RET-V804L and Ba/F3-KIF5B-RET-V804M cells were constructed by Hefei Zhongke Puruisheng Biomedical Technology Co., Ltd.
  • Ba/F3-KIF5B-RET, Ba/F3-KIF5B-RET-V804L and Ba/F3-KIF5B-RET-V804M medium RPMI-1640+10%FBS+1%P/S.
  • Cell viability(CV%) (RLU compound-RLU blank)/(RLU control-RLU blank)*100%, analyze with Graphpad 7.0 software, calculate the corresponding IC50 data, as shown in Table 2.
  • the compounds of the present invention have a good inhibitory effect on Ba/F3 (WT-RET, RET-V804L and RET-V804M), especially compounds C15 and C26.
  • SD rats were given four small molecule compounds BLU-667, compound C2, compound C4 and compound C8 once intravenously and intragastrically, respectively. Blood samples were collected at different time points to determine the concentration of the drug in the rat plasma after administration of the test substance. Calculate relevant pharmacokinetic parameters.
  • the preparation of the test substance administration solution was completed in the School of Pharmacy of Soochow University.
  • the preparation method is as follows:
  • the compound solvent code-named BLU-667, C2, C4, C8 is 10% NMP+49%PEG400+1%Tween80+40%Water.
  • the specific preparation method is as follows: Weigh an appropriate amount of the test substance and dissolve it in 10% NMP + 49% PEG400 + 1% Tween 80 + 40% Water, vortex and mix well, and set aside.
  • the prepared test solution is tested and analyzed by the analysis department of this experimental institution using LC-MS/MS.
  • Healthy male SD rats were used in the study; animal weight: 150-200 g. All animals were fasted before administration and resumed feeding 4 hours after administration.
  • the blood sampling time points are:
  • Intravenous administration (group 1, 3, 5): 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12 and 24h after administration. ( ⁇ 2hr time point ⁇ 2min, other points ⁇ 15min.)
  • Oral administration (groups 2, 4, 6, 7): 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h after administration. ( ⁇ 2hr time point ⁇ 2min, other points ⁇ 15min.)
  • Each animal collects about 0.1 mL of blood through the jugular vein each time, and uses EDTA or heparin sodium as an anticoagulant.
  • the blood samples were collected on ice and centrifuged to separate the plasma (centrifugation conditions: 5000 rpm, 6 minutes, 4°C).
  • Rat plasma samples were analyzed by LC-MS/MS by the analysis department of the experimental institution.
  • the pharmacokinetic calculation software WinNonlin non-compartmental model was used to calculate the pharmacokinetic parameters of the test product AUC 0 ⁇ t , AUC 0 ⁇ , MRT 0 ⁇ , C max , T max , Vss, F, CL and T 1/2 and their mean and standard deviation.
  • the compound of the present application has better drug metabolism, especially compound C4. Its maximum blood concentration (Cmax) and plasma exposure AUC are respectively increased by 3 to 4 times and 2 to 3 times compared with the control compound. Therefore, the compounds of the present invention have better bioavailability and are expected to be further developed as drugs for regulating RET kinase activity or treating RET-related diseases.

Abstract

The present invention belongs to the field of medical technology and specifically disclosed is a compound represented by formula (I'), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and each symbol therein is as defined in the claims. The compound of the present invention may be used as a drug for regulating RET kinase activity or treating RET-related diseases, and has better pharmacokinetic properties.

Description

用作RET激酶抑制剂的化合物及其应用Compounds used as RET kinase inhibitors and their applications 技术领域Technical field
本发明涉及医药技术领域，具体涉及用作RET激酶抑制剂的化合物，及其在调节RET激酶活性或治疗RET相关疾病方面的应用。The present invention relates to the field of medical technology, in particular to compounds used as RET kinase inhibitors, and their application in regulating RET kinase activity or treating RET-related diseases.
背景技术Background technique
RET(Rearranged during transfection，转染期间重排)基因位于10号染色体，它所编码的RET蛋白是一种存在于细胞膜上的受体酪氨酸激酶(RTK)，其变异类型主要包括与KIF5B、TRIM33、CCDC6和NCOA4等基因的融合突变，以及M918T等位点的点突变。人们常见的RET突变主要发生在甲状腺癌、非小细胞肺癌等多种癌症类型里。RET基因融合在NSCLC患者中的发生率约为1％～2％，在甲状腺***状癌(占所有甲状腺癌的85％左右)中的发生率为10％～20％，RET融合在年轻患者中更为常见，特别是年轻的非吸烟肺腺癌患者，发生率高达7％～17％。目前对于RET基因改变的治疗方案主要是使用多激酶抑制剂类药物，比如卡博替尼、凡德他尼，由于靶向性不高，通常会发生脱靶导致的VEGFR抑制相关的严重毒性。The RET (Rearranged during transfection, rearrangement during transfection) gene is located on chromosome 10. The RET protein it encodes is a receptor tyrosine kinase (RTK) that exists on the cell membrane. Its mutation types mainly include KIF5B, Fusion mutations in genes such as TRIM33, CCDC6 and NCOA4, and point mutations in M918T. Common RET mutations mainly occur in many types of cancers such as thyroid cancer and non-small cell lung cancer. The incidence of RET gene fusion in NSCLC patients is about 1% to 2%, and the incidence in papillary thyroid cancer (accounting for about 85% of all thyroid cancers) is 10% to 20%. RET fusion occurs in young patients. It is more common, especially in young non-smokers with lung adenocarcinoma, the incidence is as high as 7% to 17%. The current treatment plan for RET gene modification is mainly to use multi-kinase inhibitor drugs, such as cabozantinib and vandetanib. Due to the low targeting, severe toxicity related to VEGFR inhibition usually occurs due to off-target.
蓝图药品公司(Blueprint)和莱德克斯制药公共有限公司(Loxo Oncology)公布了其开发的高效且具有选择性的口服RET抑制剂BLU-667和LOXO-292。Blueprint I期临床数据结果显示BLU-667表现出广泛的抗肿瘤活性，在具有RET融合和突变的肿瘤患者中总体缓解率(ORR)为45％，其中非小细胞肺癌和甲状腺髓样癌患者的ORR分别为50％和40％。最近美国FDA授予Loxo Oncology公司的在研药物LOXO-292突破性疗法认定，用于治疗携带RET基因变异的非小细胞肺癌(NSCLC)和甲状腺髓样癌(MTC)患者。Blueprint and Loxo Oncology announced their development of efficient and selective oral RET inhibitors BLU-667 and LOXO-292. Blueprint Phase I clinical data showed that BLU-667 exhibits extensive anti-tumor activity. The overall response rate (ORR) in tumor patients with RET fusion and mutation is 45%. Among them, patients with non-small cell lung cancer and medullary thyroid cancer ORR is 50% and 40%, respectively. Recently, the US FDA granted Loxo Oncology's research drug LOXO-292 breakthrough therapy designation for the treatment of non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC) patients with RET gene mutations.
无论是BLU-667还是LOXO-292，目前还均处于临床试验阶段。因此，开发新的具有RET激酶抑制活性的、具有更好药效学、药代动力学性能的化合物已成为开发新型抗肿瘤药物的重要研究项目，并最终用于人类肿瘤等疾病的治疗中。Both BLU-667 and LOXO-292 are still in clinical trials. Therefore, the development of new compounds with RET kinase inhibitory activity and better pharmacodynamics and pharmacokinetic properties has become an important research project for the development of new anti-tumor drugs, and finally used in the treatment of human tumors and other diseases.
发明内容Summary of the invention
本发明提供了一种新的具有RET激酶抑制活性的、具有更好药效学、药代动力学性能的化合物。The present invention provides a new compound with RET kinase inhibitory activity and better pharmacodynamics and pharmacokinetic properties.
本发明第一方面，提供一种用作RET激酶抑制剂的化合物，所述化合物为式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，The first aspect of the present invention provides a compound for use as a RET kinase inhibitor, the compound being a compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
Figure PCTCN2020091425-appb-000001
Figure PCTCN2020091425-appb-000001
其中：among them:
R 1为取代或未取代的5-6元杂环基或5-6元杂芳基；所述取代是指任选地被一个或多个R 2取代； R 1 is a substituted or unsubstituted 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the substitution refers to optionally substituted by one or more R 2 ;
X 3选自：O、NR 8、CR 9R 10、
Figure PCTCN2020091425-appb-000002
其中，R 8和R 11各自独立地选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6卤代烷基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳烷基、C3～C6杂环烷基；R 9和R 10各自独立地选自：氢、卤素、C1～C6烷基、C1～C6卤代烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； X 3 is selected from: O, NR 8 , CR 9 R 10 ,
Figure PCTCN2020091425-appb-000002
Wherein, R 8 and R 11 are each independently selected from: hydrogen, C1～C6 alkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 haloalkyl, C1～C6 heteroalkyl, C3～C6 ring Alkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, aralkyl, C3-C6 heterocycloalkyl; R 9 and R 10 are each independently selected from: hydrogen, halogen, C1-C6 alkane Group, C1～C6 haloalkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C3～C6 cycloalkyl, C3～C6 halocycloalkyl, Aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
W环为取代或未取代的亚杂环基或亚杂芳基，所述取代是指任选地被0-2个R 5取代； Ring W is a substituted or unsubstituted heterocyclylene or heteroarylene, and the substitution means optionally substituted with 0-2 R 5 ;
环Q1任选自：3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；环Q1上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；Ring Q1 is optionally selected from: 3 to 7-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged rings, and may contain 0 to 3 heteroatoms, and heteroatoms are optionally selected from N, O, S; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～ C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl;
X 5选自：C(O)、S(O)、S(O) 2、
Figure PCTCN2020091425-appb-000003
X 5 is selected from: C(O), S(O), S(O) 2 ,
Figure PCTCN2020091425-appb-000003
X 6选自：CR 9、N、O； X 6 is selected from: CR 9 , N, O;
R 2任选自：氢、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、烷胺基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from: hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C1～C6 alkylamino, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy Group, alkylamino group, cycloalkyl group and heteroalkyl group are optionally and independently substituted with 0-5 Ra ;
A任选自：3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；A环上的任意氢原子可被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；A is optionally selected from: 3 to 7-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged rings, and may contain 0 to 3 heteroatoms, and heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 Thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl;
R 3任选自：氢、氘、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、烷胺基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 3 is optionally selected from: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each alkyl group, Alkoxy, alkylamino, cycloalkyl and heteroalkyl are optionally and independently substituted with 0-5 Ra ;
R 4各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代； R 4 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ) , -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C (O)OR 7 , -(C1～C6 alkylene) -N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 ) (R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0 to 5 R a;
R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氧代基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代； R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, oxo, cyano, -C(O)R 6 , -OC (O)R 6 , -C(O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 ) (R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P( O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, Aralkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0-5 Ra ;
R 6和R 7各自独立地选自：H、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； R 6 and R 7 are each independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkane Group, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基； R a optionally from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy group, C1 ~ C6 alkyl group, a cycloalkyl group, a heterocyclic group, or a cyano group;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
n为0或1；n is 0 or 1;
限定条件是：当环W为取代或未取代的6元杂芳基时，环W被X 4取代，其中，X 4选自：CN、
Figure PCTCN2020091425-appb-000004
The limiting condition is: when ring W is a substituted or unsubstituted 6-membered heteroaryl group, ring W is substituted by X 4 , wherein X 4 is selected from: CN,
Figure PCTCN2020091425-appb-000004
且Q1仅通过Q1环上的碳原子与环W相连。And Q1 is only connected to ring W through a carbon atom on the Q1 ring.
在另一优选例中，W环为取代或未取代的下组基团：5-6元单环亚杂环基、8-10元双环亚杂环基或5-6元单环亚杂芳基或8-10元双环亚杂芳基；所述取代是指任选地被0-2个R 5取代；R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氧代基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、- (C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基。 In another preferred example, ring W is a substituted or unsubstituted group of the following groups: 5-6 membered monocyclic heterocyclylene, 8-10 membered bicyclic heterocyclylene or 5-6 membered monocyclic heteroarylene Group or 8-10 membered bicyclic heteroarylene; the substitution refers to optionally substituted with 0-2 R 5 ; R 5 is each independently optionally selected from: hydrogen, C1-C6 alkyl, C2-C6 alkene Group, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, Heterocyclyl, heterocycloalkyl, nitro, oxo, cyano, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1～C6 alkylene Group) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ),-(C1～C6 alkylene)- S(O) 2 R 6 , -(C1～C6 alkylene) -S(O) 2 -N(R 6 )(R 7 ), -N(R 6 )(R 7 ), -C(O) -N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N (R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkyne Groups, alkoxy groups, alkylamino groups, heteroalkyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, aryloxy groups, aralkyl groups, heterocyclic groups and heterocycloalkyl groups are each independently covered by 0-5 R a substituent; R & lt optionally a from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy group, C1 ~ C6 alkyl group, a cycloalkyl group, heterocycloalkyl or cyano base.
在另一优选例中，所述式I'所示的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，W环选自：
Figure PCTCN2020091425-appb-000005
Figure PCTCN2020091425-appb-000006
其中，X 1、X 2、X 7、X 8各自独立地选自N或CR 5；且X 7、X 8中至少有一个为N； In another preferred embodiment, in the compound represented by formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the W ring is selected from:
Figure PCTCN2020091425-appb-000005
Figure PCTCN2020091425-appb-000006
Wherein, X 1 , X 2 , X 7 , and X 8 are each independently selected from N or CR 5 ; and at least one of X 7 and X 8 is N;
R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、硝基、氰基、氨基；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基；环Q2任选自：五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基。 R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl group, nitro group, cyano group, amino group; wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group and cycloalkyl group are each independently covered by 0-5 R a substituent; R & lt optionally a from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy group, C1 ~ C6 alkyl group, a cycloalkyl group, heterocycloalkyl or cyano Group; Ring Q2 is optional from: five-membered, six-membered or seven-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged ring, and may contain 0 to 3 heteroatoms, any heteroatom Any hydrogen atom selected from N, O, S, ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1- C6 haloalkyl, C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl Or heteroaryl.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(Ⅱ)、式(Ⅲ)或式(Ⅳ)所示的结构，In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has formula (II), formula (III) or formula (IV) ) Shows the structure,
Figure PCTCN2020091425-appb-000007
Figure PCTCN2020091425-appb-000007
Figure PCTCN2020091425-appb-000008
Figure PCTCN2020091425-appb-000008
其中：among them:
A任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；A is optionally selected from a saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring of 3 to 7 members, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S;
环Q1任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；环Q1上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；在式(Ⅱ)中，Q1仅通过Q1环上的碳原子与环B相连；Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 Thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl; in the formula In (II), Q1 is connected to ring B only through the carbon atom on ring Q1;
R 1任选自以下结构中的一种： R 1 is optionally selected from one of the following structures:
Figure PCTCN2020091425-appb-000009
Figure PCTCN2020091425-appb-000009
Figure PCTCN2020091425-appb-000010
Figure PCTCN2020091425-appb-000010
R 2任选自氢、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl The group is optionally and independently substituted with 0-5 Ra ;
R 3任选自氢、氘、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 3 is optionally selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each of alkyl, alkoxy, cycloalkyl and Heteroalkyl is optionally and independently substituted with 0-5 Ra ;
R a任选自C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、环烷基、杂环烷基或氰基； R a is optionally selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano;
X 1、X 2各自独立地选自N或CR 5； X 1 and X 2 are each independently selected from N or CR 5 ;
X 3选自O、NR 8、CR 9R 10、
Figure PCTCN2020091425-appb-000011
其中R 8和R 11各自独立地选自氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6卤代烷基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳烷基、C3～C6杂环烷基；R 9和R 10各自独立地选自氢、卤素、C1～C6烷基、C1～C6卤代烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； X 3 is selected from O, NR 8 , CR 9 R 10 ,
Figure PCTCN2020091425-appb-000011
Wherein R 8 and R 11 are each independently selected from hydrogen, C1～C6 alkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 haloalkyl, C1～C6 heteroalkyl, C3～C6 cycloalkyl , C3-C6 halocycloalkyl, aryl, heteroaryl, aralkyl, C3-C6 heterocycloalkyl; R 9 and R 10 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1 ～C6 haloalkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C3～C6 cycloalkyl, C3～C6 halocycloalkyl, aryl, Heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
X 4选自CN、
Figure PCTCN2020091425-appb-000012
X 4 is selected from CN,
Figure PCTCN2020091425-appb-000012
X 5选自C(O)、S(O)、S(O) 2、
Figure PCTCN2020091425-appb-000013
X 5 is selected from C(O), S(O), S(O) 2 ,
Figure PCTCN2020091425-appb-000013
X 6选自CR 9、N、O； X 6 is selected from CR 9 , N, O;
R 4、R 5各自独立地任选自氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚 烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R 6和R 7各自独立地选自C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 heteroalkyl, cycloalkyl , Aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C( O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl is each Independently substituted by 0-5 Ra ; R 6 and R 7 are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hetero Alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
环Q2任选自五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；Ring Q2 is optionally selected from a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N , O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl , C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl base;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
n为0或1。n is 0 or 1.
在另一优选例中，X 3为NR 8，其中，R 8为H。 In another preferred embodiment, X 3 is NR 8 , wherein R 8 is H.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(2)、式(3)或式(4)所示的结构，In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has formula (2), formula (3) or formula (4) ) Shows the structure,
Figure PCTCN2020091425-appb-000014
Figure PCTCN2020091425-appb-000014
Figure PCTCN2020091425-appb-000015
Figure PCTCN2020091425-appb-000015
其中：among them:
A任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；A is optionally selected from a saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring of 3 to 7 members, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S;
环Q1任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；环Q1上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；在式(2)中，Q1仅通过Q1环上的碳原子与环B相连；Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 Thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl; in the formula In (2), Q1 is connected to ring B only through the carbon atom on ring Q1;
R 1任选自以下结构中的一种： R 1 is optionally selected from one of the following structures:
Figure PCTCN2020091425-appb-000016
Figure PCTCN2020091425-appb-000016
R 2任选自氢、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl The group is optionally and independently substituted with 0-5 Ra ;
R 3任选自氢、氘、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 3 is optionally selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each of alkyl, alkoxy, cycloalkyl and Heteroalkyl is optionally and independently substituted with 0-5 Ra ;
R a任选自C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、环烷 基、杂环烷基或氰基； R a is optionally selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano;
X 1、X 2各自独立地选自N或CR 5； X 1 and X 2 are each independently selected from N or CR 5 ;
R 4、R 5各自独立地任选自氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R 6和R 7各自独立地选自C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 heteroalkyl, cycloalkyl , Aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C( O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl is each Independently substituted by 0-5 Ra ; R 6 and R 7 are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hetero Alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
环Q2任选自五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；Ring Q2 is optionally selected from a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N , O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl , C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl base;
m为0、1、2、3、4、5或6。m is 0, 1, 2, 3, 4, 5 or 6.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，W环选自下组：
Figure PCTCN2020091425-appb-000017
Figure PCTCN2020091425-appb-000018
Figure PCTCN2020091425-appb-000019
In another preferred example, the W ring of the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, is selected from the following group:
Figure PCTCN2020091425-appb-000017
Figure PCTCN2020091425-appb-000018
Figure PCTCN2020091425-appb-000019
其中，
Figure PCTCN2020091425-appb-000020
为单键或双键； among them,
Figure PCTCN2020091425-appb-000020
Single bond or double bond;
R 12独立地选自：H、卤素、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、硝基、氰基、氨基； R 12 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, amino;
各Y 1、Y2、Y3独立地选自：O、N、NR 17、CR 13、CR 13R 14 Each Y 1 , Y2 and Y3 is independently selected from: O, N, NR 17 , CR 13 , CR 13 R 14
R 13、R 14、R 15、R 16各自独立地选自：H、卤素、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、硝基、氰基、氨基；或者R 13和R 14与其连接的C原子一起形成羰基(C＝O)；或者R 15和R 16与其连接的C原子一起形成羰基(C＝O)； R 13 , R 14 , R 15 , and R 16 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, amino; or R 13 and R 14 together with the C atom to which they are connected form a carbonyl group (C=O); or R 15 and R 16 together with the C atom to which they are connected form a carbonyl group (C=O);
R 17选自：H、C1～C6烷基。 R 17 is selected from: H, C1-C6 alkyl.
在另一优选例中，W环选自：
Figure PCTCN2020091425-appb-000021
In another preferred embodiment, the W ring is selected from:
Figure PCTCN2020091425-appb-000021
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式2'所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2'
Figure PCTCN2020091425-appb-000022
Figure PCTCN2020091425-appb-000022
其中，
Figure PCTCN2020091425-appb-000023
为单键或双键； among them,
Figure PCTCN2020091425-appb-000023
Single bond or double bond;
各R 17独立地选自：氘、卤素、羟基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基； Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
f为0、1、2、3、4、5、6、7、8或9；f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
X 1、X 2、R 1、R 2、R 3、R 4、A和m的定义如上所述。 The definitions of X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , A and m are as described above.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式2”所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2"
Figure PCTCN2020091425-appb-000024
Figure PCTCN2020091425-appb-000024
其中，among them,
R 1、R 2、R 3、R 4、A、m、X 1、X 2和R 17的定义如上所述。 The definitions of R 1 , R 2 , R 3 , R 4 , A, m, X 1 , X 2 and R 17 are as described above.
在另一优选例中，
Figure PCTCN2020091425-appb-000025
选自：
Figure PCTCN2020091425-appb-000026
R 12的定义如上所述。 In another preferred example,
Figure PCTCN2020091425-appb-000025
Selected from:
Figure PCTCN2020091425-appb-000026
The definition of R 12 is as described above.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式3'所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3'
Figure PCTCN2020091425-appb-000027
Figure PCTCN2020091425-appb-000027
其中，
Figure PCTCN2020091425-appb-000028
为单键或双键； among them,
Figure PCTCN2020091425-appb-000028
Single bond or double bond;
Figure PCTCN2020091425-appb-000029
为单键时，Y 4选自：N或CR 17，
Figure PCTCN2020091425-appb-000029
When it is a single bond, Y 4 is selected from: N or CR 17 ,
Figure PCTCN2020091425-appb-000030
为双键时，Y 4为C；
Figure PCTCN2020091425-appb-000030
When it is a double bond, Y 4 is C;
各R 17独立地选自：氘、卤素、羟基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基； Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
f为0、1、2、3、4、5、6、7、8或9；f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
p为0、1、2、3；p is 0, 1, 2, 3;
X 2、Q2、R 1、R 2、R 3、R 4、A和m的定义如上所述。 X 2 , Q2, R 1 , R 2 , R 3 , R 4 , A and m are defined as described above.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式3”所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3"
Figure PCTCN2020091425-appb-000031
Figure PCTCN2020091425-appb-000031
R 1、X 2、R 2、R 3、R 4、A、Q2、m和R 17的定义如上所述。 R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
在另一优选例中，
Figure PCTCN2020091425-appb-000032
部分选自：
Figure PCTCN2020091425-appb-000033
Figure PCTCN2020091425-appb-000034
In another preferred example,
Figure PCTCN2020091425-appb-000032
Partly selected from:
Figure PCTCN2020091425-appb-000033
Figure PCTCN2020091425-appb-000034
其中，
Figure PCTCN2020091425-appb-000035
为单键或双键； among them,
Figure PCTCN2020091425-appb-000035
Single bond or double bond;
Y 1、Y 2、Y 3、R 12、R 13、R 14、R 15和R 16的定义如上所述。 The definitions of Y 1 , Y 2 , Y 3 , R 12 , R 13 , R 14 , R 15 and R 16 are as described above.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式4'所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 4'
Figure PCTCN2020091425-appb-000036
Figure PCTCN2020091425-appb-000036
其中，
Figure PCTCN2020091425-appb-000037
为单键或双键； among them,
Figure PCTCN2020091425-appb-000037
Single bond or double bond;
Figure PCTCN2020091425-appb-000038
为单键时，Y 4选自：N或CR 17；
Figure PCTCN2020091425-appb-000038
When it is a single bond, Y 4 is selected from: N or CR 17 ;
Figure PCTCN2020091425-appb-000039
为双键时，Y 4为C；
Figure PCTCN2020091425-appb-000039
When it is a double bond, Y 4 is C;
各R 17独立地选自：氘、卤素、羟基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基； Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
f为0、1、2、3、4、5、6、7、8或9；f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
p为0、1、2、3；p is 0, 1, 2, 3;
X 2、Q2、R 1、R 2、R 3、R 4、A和m的定义如上所述。 X 2 , Q2, R 1 , R 2 , R 3 , R 4 , A and m are defined as described above.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式4”所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4"
Figure PCTCN2020091425-appb-000040
Figure PCTCN2020091425-appb-000040
R 1、X 2、R 2、R 3、R 4、A、Q2、m和R 17的定义如上所述。 R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
在另一优选例中，
Figure PCTCN2020091425-appb-000041
部分为
Figure PCTCN2020091425-appb-000042
其中，Q 2的定义如上所述。 In another preferred example,
Figure PCTCN2020091425-appb-000041
Partly
Figure PCTCN2020091425-appb-000042
Here, the definition of Q 2 is as described above.
在另一优选例中，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式5、式6所示的结构：In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5 and formula 6:
Figure PCTCN2020091425-appb-000043
Figure PCTCN2020091425-appb-000043
其中，R 1、X 7、X 8、X 2、Q2、R 2、R 3、R 4、R 17、A和m的定义如上所述，且X 7、X 8中至少有一个为N。 Wherein, R 1 , X 7 , X 8 , X 2 , Q2, R 2 , R 3 , R 4 , R 17 , A and m are as defined above, and at least one of X 7 and X 8 is N.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，A为芳香环、杂芳环，所述杂芳环含有0～3个杂原子，杂原子任选自N、O、S；A环上的任意氢原子可被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基。In another preferred embodiment, in the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, A is an aromatic ring, a heteroaromatic ring, and the heteroaromatic ring contains 0 to 3 heteroatoms, heteroatoms can be selected from N, O, S; any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, Amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl.
在另一优选例中，A为苯基、吡啶基、吡嗪基、嘧啶基或哒嗪基，A环上的任意氢原子可被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基。In another preferred example, A is phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, and any hydrogen atom on ring A can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester Group, amide group, ketone carbonyl group, amino group, C1～C6 alkyl group, C1～C6 haloalkyl group, C1～C6 thioalkyl group, C1～C6 alkoxy group, C1～C6 heteroalkyl group, C1～C6 alkylamino group , C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，R 4各自独立地任选自：芳基、杂芳基、芳氧基、芳烷基、杂环基；其中，每个芳基、杂芳基、芳氧基、芳烷基、杂环基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基。 In another preferred embodiment, in the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, R 4 is each independently selected from: aryl, heteroaryl , an aryloxy group, an aralkyl group, a heterocyclic group; wherein each aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl independently substituted with 0 to 5 R a; R a to any Selected from: C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
在另一优选例中，R 4为5元杂芳基，所述的杂芳基可以被独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基。 In another preferred embodiment, R 4 is 5-membered heteroaryl group, the heteroaryl group may be independently substituted with 0 to 5 R a; R a optionally from: C1 ~ C6 alkyl group, halo, hydroxy , C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
在另一优选例中，R 4选自：
Figure PCTCN2020091425-appb-000044
其中，R 18选自：卤素(优选地为F)、C1～C6烷基。 In another preferred embodiment, R 4 is selected from:
Figure PCTCN2020091425-appb-000044
Wherein, R 18 is selected from: halogen (preferably F), C1-C6 alkyl.
在另一优选例中，m为1。In another preferred example, m is 1.
在另一优选例中，R 3为H、C1-C6烷基、C1-C6烷氧基。 In another preferred embodiment, R 3 is H, C1-C6 alkyl, C1-C6 alkoxy.
在另一优选例中，R 2为H。 In another preferred embodiment, R 2 is H.
在另一优选例中，R 1、X 3、W、Q1、X 5、X 6、R 2、R 3、R 4、A、m和n为实施例中各具体化合物相对应的具体基团。 In another preferred embodiment, R 1 , X 3 , W, Q1, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are specific groups corresponding to the specific compounds in the embodiments .
在另一优选例中，R 1、X 1、X 2、X 3、Q1、Q2、X 5、X 6、R 2、R 3、R 4、A、m和n为实施例中各具体化合物相对应的具体基团。 In another preferred embodiment, R 1 , X 1 , X 2 , X 3 , Q1, Q2, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are specific compounds in the embodiment The corresponding specific group.
在另一优选例中，
Figure PCTCN2020091425-appb-000045
部分为
Figure PCTCN2020091425-appb-000046
其中，X 9、X 10各自独立地选自N或CR 5，其中，R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、硝基、氰基、氨基；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基。 In another preferred example,
Figure PCTCN2020091425-appb-000045
Partly
Figure PCTCN2020091425-appb-000046
Wherein, X 9 and X 10 are each independently selected from N or CR 5 , wherein each of R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, C1～C6 alkylamino, halogen, C1～C6 heteroalkyl, cycloalkyl, nitro, cyano, amino; wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkane amino, heteroalkyl, cycloalkyl independently substituted with 0 to 5 R a; R a optionally from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy Group, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
在另一优选例中，所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式5'或者6'所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula 5'or 6'
Figure PCTCN2020091425-appb-000047
Figure PCTCN2020091425-appb-000047
其中，X 2、X 7、X 8、X 9、X 10各自独立地选自：N或CR 5，且X 7、X 8至少有一个 为N， Wherein, X 2 , X 7 , X 8 , X 9 , and X 10 are each independently selected from: N or CR 5 , and at least one of X 7 and X 8 is N,
R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、硝基、氰基、氨基；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基； R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl group, nitro group, cyano group, amino group; wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group and cycloalkyl group are each independently covered by 0-5 R a substituent; R & lt optionally a from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy group, C1 ~ C6 alkyl group, a cycloalkyl group, heterocycloalkyl or cyano base;
环Q2任选自：五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基。Ring Q2 is optionally selected from: a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkane Group, C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or hetero Aryl.
在另一优选例中，
Figure PCTCN2020091425-appb-000048
部分选自：
Figure PCTCN2020091425-appb-000049
Figure PCTCN2020091425-appb-000050
Figure PCTCN2020091425-appb-000051
Y 2、Y 3、R 12的定义如上所述。 In another preferred example,
Figure PCTCN2020091425-appb-000048
Partly selected from:
Figure PCTCN2020091425-appb-000049
Figure PCTCN2020091425-appb-000050
Figure PCTCN2020091425-appb-000051
The definitions of Y 2 , Y 3 , and R 12 are as described above.
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，可以任选自以下结构所示的化合物：In another preferred embodiment, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be selected from the compound represented by the following structure:
Figure PCTCN2020091425-appb-000052
Figure PCTCN2020091425-appb-000052
Figure PCTCN2020091425-appb-000053
Figure PCTCN2020091425-appb-000053
Figure PCTCN2020091425-appb-000054
Figure PCTCN2020091425-appb-000054
Figure PCTCN2020091425-appb-000055
Figure PCTCN2020091425-appb-000055
在另一优选例中，所述化合物选自实施例中所示的化合物。In another preferred example, the compound is selected from the compounds shown in the examples.
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，药学上可接受的盐为无机酸盐或有机酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。In another preferred embodiment, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; the organic acid salt is selected from formate, ethyl Acid salt, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, Citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
本发明第二方面，提供一种药物组合物，其含有治疗有效量的第一方面所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，以及药学上可接受的载体。In the second aspect of the present invention, there is provided a pharmaceutical composition containing a therapeutically effective amount of the compound of formula I'described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, And a pharmaceutically acceptable carrier.
在另一优选例中，所述的药物组合物还可以包含一种或多种其他治疗剂，所述的其他治疗剂选自：PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB- A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。In another preferred embodiment, the pharmaceutical composition may also contain one or more other therapeutic agents, and the other therapeutic agents are selected from: PD-1 inhibitors (such as nivolumab, pembrolizumab) , JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 Inhibitors (such as Devaluzumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs Etc.), CD20 antibodies (such as rituximab, obin eutuzumab, ofatumumab, tositumomab, ibritumomab, etc.), CD47 antibodies (such as Hu5F9-G4, CC -90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib) , Brigatinib, loratinib, okatinib), PI3K inhibitors (such as Idelaris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, etc.) , EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, etc.), VEGFR inhibitors (such as sola Fini, pazopanib, revatinib, cabozantinib, sunitinib, donafinib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, daxilast, Tektronix, etc.) Denarin, etc.), CDK inhibitors (e.g. Pabocinil, Ribocinil, Abemaciclib, Lerociclib, etc.), MEK inhibitors (e.g. Smeltinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC- 4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.) or combinations thereof.
本发明第三方面，提供一种如第一方面所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于RET激酶抑制剂药物方面的应用。In the third aspect of the present invention, there is provided a compound of formula I'as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof for the preparation of a RET kinase inhibitor drug Applications.
本发明第四方面，提供一种如第一方面所述的式I'的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于调节RET激酶活性或治疗RET相关疾病药物方面的应用。In the fourth aspect of the present invention, there is provided a compound of formula I'as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in preparation for regulating RET kinase activity or Application of drugs to treat RET-related diseases.
在另一优选例中，所述的RET相关疾病包括癌症。In another preferred embodiment, the RET-related diseases include cancer.
在另一优选例中，所述癌症为甲状腺癌或肺癌。In another preferred embodiment, the cancer is thyroid cancer or lung cancer.
在另一优选例中，所述癌症为甲状腺髓样癌或非小细胞肺癌。In another preferred example, the cancer is medullary thyroid carcinoma or non-small cell lung cancer.
具体实施方式Detailed ways
本发明人经过广泛而深入的研究，意外地发现了一类具有较好的RET激酶抑制活性的化合物。此外，所述化合物对RET激酶具有优异的抑制活性，并且具有更好药效学/药代动力学性能。在此基础上，完成了本发明。After extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with better RET kinase inhibitory activity. In addition, the compound has excellent inhibitory activity on RET kinase, and has better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.
术语the term
除非特别说明，否则在本申请中(包括说明书和权利要求书)所用的以下术语具有下面所给出的定义。Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左 书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
“烷基(单独或作为其他基团的一部分)”指的是仅由碳和氢原子组成的含有1至12个碳原子的单价直链或支链饱和烃基团。烷基优先选地为C1-C6烷基(即包含1、2、3、4、5或6个碳原子)。烷基基团的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、正己基、辛基、十二烷基等。本申请中，烷基还意在包含取代烷基，即烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。“卤代烷基”指的是其中一个或多个氢被相同或不同的卤素代替的本文所定义的烷基。卤代烷基的实例包括-CH 2Cl、-CH 2CF 3、-CH 2CCl 3、全氟烷基(例如，-CF 3)等。 "Alkyl (alone or as part of other groups)" refers to a monovalent linear or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms and containing 1 to 12 carbon atoms. The alkyl group is preferably a C1-C6 alkyl group (ie, contains 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl and the like. In this application, an alkyl group is also intended to include a substituted alkyl group, that is, one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyl groups include -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl (for example, -CF 3 ), and the like.
“亚烷基”是指烷基的二价基团，例如-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-。 "Alkylene" refers to a divalent group of an alkyl group, such as -CH 2 -, -CH 2 CH 2 -and -CH 2 CH 2 CH 2 -.
“烷氧基(单独或作为其他基团的一部分)”是指其上连接有氧基的烷基，其具有烷基O-结构，其中，烷基具有如上所述的定义优选地，烷氧基为C1～C6烷氧基。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、叔丁氧基等。“卤代烷氧基”指的是式-OR基团，其中R是本文所定义的卤代烷基基团。卤代烷氧基基团的实例包括但不限于三氟甲氧基、二氟甲氧基、2,2,2-三氟乙氧基等。"Alkoxy (alone or as part of another group)" refers to an alkyl group to which an oxy group is attached, which has an alkyl O- structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group The group is a C1-C6 alkoxy group. Alkoxy includes but is not limited to methoxy, ethoxy, propoxy, tert-butoxy and the like. "Haloalkoxy" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
“硫代烷基”是指烷基中的碳被S、S(O)或S(O)2所取代。"Thioalkyl" means that the carbon in the alkyl group is replaced by S, S(O) or S(O)2.
“烯基(单独或作为其他基团的一部分)”是指含有至少一个双键的脂族基团，通常具有为2至20个碳原子。本发明中，“C2-C6烯基”是指含有2、3、4、5或6个碳原子的烯基。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中，烯基包括取代的烯基。"Alkenyl (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, usually having 2 to 20 carbon atoms. In the present invention, "C2-C6 alkenyl" refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like. In the present invention, alkenyl includes substituted alkenyl.
“亚烯基”是指具有两个连接点的烯基。例如，“亚乙烯基”表示基团-CH＝CH-。亚烯基也可是未取代的形式或具有一个或多个取代基的取代形式。"Alkenylene" refers to an alkenyl group having two points of attachment. For example, "vinylene" means the group -CH=CH-. The alkenylene group may also be in an unsubstituted form or a substituted form with one or more substituents.
“炔基(单独或作为其他基团的一部分)”是指含有2个以上碳原子且特征为具有一个或多个三键的直链或支链烃链，通常具有为2至20个碳原子。本发明中，“C2-6炔基”是指具有2、3、4、5或6个碳原子的炔基。炔基包括但不限于是乙炔基、炔丙基和3-己炔基。三键碳中的一个可以任选地为炔基取代基的连接点。本发明中，炔基还包括取代炔基。"Alkynyl (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by one or more triple bonds, usually having 2 to 20 carbon atoms . In the present invention, "C2-6 alkynyl" refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent. In the present invention, alkynyl groups also include substituted alkynyl groups.
“亚炔基”是指具有两个连接点的炔基。例如“亚乙炔基”表示基团：-C≡C-。亚炔基也可是未取代的形式或具有一个或多个取代基的取代形式。"Alkynylene" refers to an alkynyl group having two points of attachment. For example, "ethynylene" means the group: -C≡C-. The alkynylene group may also be in an unsubstituted form or a substituted form with one or more substituents.
“脂族基团”是指直链、支链或环状烃基，包括饱和及不饱和基团，如烷基、烯基和炔基。"Aliphatic group" refers to a straight chain, branched chain or cyclic hydrocarbon group, including saturated and unsaturated groups such as alkyl, alkenyl and alkynyl groups.
“芳环***”是指单环、双环或多环烃环***，其中至少一个环是芳族的。"Aromatic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.
“芳基(单独或作为其他基团的一部分)”是指芳环***的一价基团。代表性芳基包括全芳环***，如苯基、萘基和蒽基；及其中芳族碳环与一个或多个非芳族碳环稠合的环***，如茚满基、邻苯二甲酰亚胺基、萘基亚胺基或四氢萘基等等。本发明 中，芳基优选地为C6-C12芳基。本发明中，芳基还意在包含取代芳基。"Aryl (alone or as part of another group)" refers to a monovalent group of an aromatic ring system. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl; and ring systems in which an aromatic carbocyclic ring is fused with one or more non-aromatic carbocyclic rings, such as indanyl and phthalyl Carboximide group, naphthyl imino group or tetrahydronaphthyl group and so on. In the present invention, the aryl group is preferably a C6-C12 aryl group. In the present invention, the aryl group is also intended to include substituted aryl groups.
“芳基烷基”或“芳烷基”是指其中烷基氢原子被芳基取代的烷基部分。芳烷基包括其中一个或以上氢原子被芳基取代的基团，芳基和烷基具有如上所述的定义。“芳基烷基”或“芳烷基”的实例包括苄基、2-苯基乙基、3-苯基丙基、9-芴基、二苯甲基和三苯甲基等。"Arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. The aralkyl group includes a group in which one or more hydrogen atoms are replaced by an aryl group, and the aryl group and the alkyl group have the definitions described above. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, trityl and the like.
“芳氧基”是指-O-(芳基)，其中芳基部分如本文所定义。"Aryloxy" refers to -O-(aryl), where the aryl moiety is as defined herein.
“杂烷基”是指被取代的烷基，其具有一个或多个选自除碳以外的原子的骨架链原子，例如，氧、氮、硫、磷或其组合。可以给出数值范围，例如，C1-C6杂烷基是指链中的碳数目，其包括1至6个碳原子。例如-CH 2OCH 2CH 3基团被称为“C3”杂烷基。与分子其余部分的连接可以通过杂烷基链中的杂原子或碳。“杂亚烷基”是指任选被取代的二价烷基，其具有一个或多个选自除碳以外的原子的骨架链原子，例如，氧、氮、硫、磷或其组合。 "Heteroalkyl" refers to a substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Numerical ranges can be given, for example, C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, the -CH 2 OCH 2 CH 3 group is referred to as a "C3" heteroalkyl. The connection to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl chain. "Heteroalkylene" refers to an optionally substituted divalent alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof.
“碳环***”是指单环、二环或多环烃环***，其中每个环是完全饱和的或含有一个或多个不饱和单元，但其中环都不是芳族的。"Carbocyclic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, in which each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic.
“碳环基”是指碳环***的一价基团。例如包括环烷基(环戊基、环丁基、环丙基、环己基等)和环烯基(例如，环戊烯基、环己烯基、环戊二烯基等)。"Carbocyclyl" refers to a monovalent group of a carbocyclic ring system. Examples include cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (for example, cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).
“环烷基”指的是由单-或二环组成的单价饱和碳环基团，其具有3-12个、优选3-10个、更优选3-6个环原子。环烷基可以任选地被一个或多个取代基所取代，其中各取代基独立地为羟基、烷基、烷氧基、卤素、卤代烷基、氨基、单烷基氨基或二烷基氨基。环烷基基团的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。"Cycloalkyl" refers to a monovalent saturated carbocyclic group composed of a mono- or bicyclic ring, which has 3-12, preferably 3-10, more preferably 3-6 ring atoms. Cycloalkyl groups may be optionally substituted with one or more substituents, where each substituent is independently a hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
“环烷氧基”指的是式-OR基团，其中R为如本文所定义的环烷基。示例性的环烷基氧基包括环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。“环烷基烷基”是指其中环烷基和烷基如本文所公开的-(环烷基)-烷基。“环烷基烷基”通过环烷基与母体分子结构键合。"Cycloalkoxy" refers to a group of formula -OR, where R is a cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Cycloalkylalkyl" refers to -(cycloalkyl)-alkyl in which cycloalkyl and alkyl are as disclosed herein. "Cycloalkylalkyl" is bonded to the parent molecular structure through a cycloalkyl group.
“杂芳环***”是指单环(如5或6元)、双环(6-12元)或多环***，其中至少一个环既为芳族的又包含至少一个杂原子(例如，N、O或S)；且其中其它环都不是杂环基(如下所定义)。在某些情况下，作为芳族的且包含杂原子的环在所述环中含有1、2、3或4个环杂原子。其至少有一个环是杂芳族的，其余环可以是饱和、部分不饱和或完全不饱和环。"Heteroaromatic ring system" refers to a single ring (e.g. 5 or 6 membered), bicyclic (6-12 membered) or polycyclic ring system, in which at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O or S); and none of the other rings are heterocyclic groups (as defined below). In some cases, rings that are aromatic and contain heteroatoms contain 1, 2, 3, or 4 ring heteroatoms in the ring. At least one ring is heteroaromatic, and the remaining rings can be saturated, partially unsaturated or fully unsaturated.
“杂芳基”指的是5至12个环原子的单环(如5或6元)、二环(如8-10元)或三环基团，其含有至少1个包含1、2或3个选自N、O或S的环杂原子、剩余的环原子是C的芳环，应当清楚地是，杂芳基的连接点应当位于芳环上。杂芳基基团的实例包括但不限于：咪唑基、
Figure PCTCN2020091425-appb-000056
唑基、异
Figure PCTCN2020091425-appb-000057
唑基、噻唑基、异噻唑基、
Figure PCTCN2020091425-appb-000058
二唑基、噻二唑基、吡嗪基、噻吩基、呋喃基、吡喃基、吡啶基、吡咯基、吡唑基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、苯并呋喃基、苯并噻吩基、苯并噻喃基、苯并咪唑基、苯并
Figure PCTCN2020091425-appb-000059
唑 基、苯并
Figure PCTCN2020091425-appb-000060
二唑基、苯并噻唑基、苯并噻二唑基、苯并吡喃基、吲哚基、异吲哚基、***基、三嗪基、喹喔啉基、嘌呤基、喹唑啉基、喹嗪基、萘啶基、蝶啶基、咔唑基、氮杂
Figure PCTCN2020091425-appb-000061
基、二氮杂
Figure PCTCN2020091425-appb-000062
基、吖啶基等。亚杂芳基是指具有两个连接位点的杂芳基。 "Heteroaryl" refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (e.g., 8-10 membered) or tricyclic group of 5 to 12 ring atoms, which contains at least one group consisting of 1, 2, or The 3 ring heteroatoms selected from N, O or S, and the remaining ring atoms are the aromatic ring of C. It should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl,
Figure PCTCN2020091425-appb-000056
Azolyl, iso
Figure PCTCN2020091425-appb-000057
Azolyl, thiazolyl, isothiazolyl,
Figure PCTCN2020091425-appb-000058
Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, Benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo
Figure PCTCN2020091425-appb-000059
Azolyl, benzo
Figure PCTCN2020091425-appb-000060
Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazoline Group, quinazinyl, naphthyridinyl, pterridinyl, carbazolyl, aza
Figure PCTCN2020091425-appb-000061
Base, diaza
Figure PCTCN2020091425-appb-000062
Base, acridinyl, etc. Heteroarylene refers to a heteroaryl group having two attachment sites.
“杂环***”是指单环、双环和多环***，其中至少一个环是饱和的或部分不饱和的(但非芳族的)且该环包含至少一个杂原子。杂环***可连接至任何杂原子或碳原子处的侧基，这产生了稳定的结构并且任一环原子可任选地被取代。"Heterocyclic ring system" refers to monocyclic, bicyclic and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and the ring contains at least one heteroatom. The heterocyclic ring system can be attached to any heteroatom or pendant group at a carbon atom, which results in a stable structure and any ring atom can be optionally substituted.
“杂环基”是指杂环***的一价基团，通常指稳定的单环(如3-8元，即3元、4元、5元、6元、7元或8元)或二环(如5-12元，即5元、6元、7元、8元、9元、10元、11元或12元)或元多环(如7-14元，即7元、8元、9元、10元、11元、12元、13元或14)，包括稠环、螺环和/或桥环结构，其为饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子。代表性杂环基包括以下环***，其中(1)每个环为非芳族的且至少一个环包含杂原子，例如，四氢呋喃基、四氢吡喃基、四氢噻吩基、吡咯烷基、吡咯烷酮基、哌啶基、吡咯啉基、十氢喹啉基、噁唑烷基、哌嗪基、二噁烷基、二氧戊环基、二吖庚因基、噁吖庚因基、噻吖庚因基、吗啉基和奎宁环基；(2)至少一个环是非芳族的且包含杂原子并且至少一个其它环是芳族碳环，例如，1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基；及(3)至少一个环是非芳族的且包含杂原子并且至少一个其它环是芳族的且包含杂原子，例如，3,4-二氢-1H-吡喃并[4,3-c]吡啶和1,2,3,4-四氢-2,6-二氮杂萘。亚杂环基是指具有两个连接位点的杂环基。本发明中，优选地亚杂环基为双环，其中一个环为杂芳基，且通过杂芳基与通式中的其他部分相连。本发明中，优选地亚杂环基为5-6元单环亚杂环基或8-10元双环亚杂环基。"Heterocyclic group" refers to a monovalent group of a heterocyclic ring system, usually refers to a stable monocyclic ring (such as 3-8 members, that is, 3, 4, 5, 6, 7 or 8 members) or two Ring (such as 5-12 yuan, that is 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered) or multi-membered ring (such as 7-14 yuan, that is 7-membered, 8-membered , 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14), including fused ring, spiro ring and/or bridged ring structure, which are saturated, partially unsaturated, and contain carbon atoms and 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S. Representative heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, Pyrrolidone, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepinyl, oxazepinyl, thiol Azepinyl, morpholinyl and quinuclidinyl; (2) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetra Hydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is aromatic and contains heteroatoms, for example , 3,4-Dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthalene. Heterocyclylene refers to a heterocyclic group having two attachment sites. In the present invention, it is preferable that the heterocyclylene is a bicyclic ring, one of which is a heteroaryl group, and is connected to the other part of the general formula through the heteroaryl group. In the present invention, the heterocyclylene is preferably a 5-6 membered monocyclic heterocyclylene or an 8-10 membered bicyclic heterocyclylene.
“杂环基烷基”是指被杂环基取代的烷基，其中，杂环基和烷基的定义如上所述。"Heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the definitions of the heterocyclic group and the alkyl group are as described above.
“烷胺基”是指具有烷基-NR-结构的基团，其中，R为H、或如上所述的烷基、环烷基、芳基、杂芳基等。"Alkylamino" refers to a group having an alkyl-NR- structure, wherein R is H, or an alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc. as described above.
“环烷胺基”指的是式-NRaRb基团，其中，Ra为H、如本文所定义的烷基或如本文所定义的环烷基，Rb为如本文所定义的环烷基，或者Ra和Rb与其连接的N原子一起形成3-10元含N单环或双环杂环基，如四氢吡咯基。如本发明所用，C3～C8环烷胺基是指含有3-8个碳原子的胺基。"Cycloalkylamino" refers to a group of formula -NRaRb, wherein Ra is H, alkyl as defined herein, or cycloalkyl as defined herein, Rb is cycloalkyl as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrolyl. As used in the present invention, a C3-C8 cycloalkylamino group refers to an amino group containing 3-8 carbon atoms.
在本发明中，“酯基”是指具有-C(O)-O-R或R-C(O)-O-结构，其中，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。In the present invention, "ester group" refers to a structure -C(O)-OR or RC(O)-O-, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , Heterocyclic group, as defined above.
在本发明中，术语“酰胺基”是指带有结构-CONRR'的基团，其中，R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。In the present invention, the term "amide group" refers to a group with the structure -CONRR', wherein R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkane Group, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R'may be the same or different in the dialkylamine segment.
在本发明中，术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环 或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。 In the present invention, the term "sulfonamide group" refers to a group with the structure -SO 2 NRR', wherein R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
“酮羰基”是指R-C(＝O)-，其中R为如上所述的烷基、环烷基等。"Ketocarbonyl" refers to R-C(=O)-, where R is alkyl, cycloalkyl, etc. as described above.
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。When a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to Alkyleneoxy and so on.
在本发明中，上述的烷基、烷氧基、环烷基、杂烷基、芳基、杂芳基、环杂烷基、烯基、炔烃、杂环、杂环基等中各基团可以是取代的或未取代的。In the present invention, the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclic group, etc. Groups can be substituted or unsubstituted.
本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、氰基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e，P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中，R a可以独立表示氢、氘、烷基、环烷基、烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。 In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Cyano, nitro, oxo (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(= O) R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S( ＝O) 2 R e , NR b P(＝O) 2 R e , S(＝O) 2 NR b R c , P(＝O) 2 NR b R c , C(＝O)OR d , C( = O) R a, C ( = O) NR b R c, OC (= O) R a, OC (= O) NR b R c, NR b C (= O) OR e, NR d C (= O )NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , where Ra can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic ring, and R b , R c and Rd can independently represent hydrogen, deuterium, alkane Group, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocycle; R e can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or Aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 ureido and so on.
“氰基”是指-CN基团。"Cyano" refers to the -CN group.
“硝基”是指-NO 2。 "Nitro" refers to -NO 2 .
“羟基”是指-OH。"Hydroxy" refers to -OH.
“氨基”是指-NH 2或RNH-，其中R为酮羰基、磺酰基、磺酰胺基、R a-C(＝O)-、R aR bN-C(＝O)-等，其中R a和R b为烷基、环烷基、芳基或杂芳基等。 "Amino" refers to -NH 2 or RNH-, where R is a ketone carbonyl group, a sulfonyl group, a sulfonamide group, R a -C (= O) -, R a R b NC (= O) - , etc., wherein R a And R b is alkyl, cycloalkyl, aryl or heteroaryl, etc.
“卤素(卤代)”是指任何卤素的基团，例如，-F、-Cl、-Br或-I。"Halogen (halo)" refers to any halogen group, for example, -F, -Cl, -Br, or -I.
“氘代物”指的是化合物中一个氢原子(H)或多个氢原子(H)被氘原子(D)取代后所得到的化合物。"Deuterated compound" refers to a compound obtained by replacing one hydrogen atom (H) or multiple hydrogen atoms (H) with deuterium atoms (D) in a compound.
在本发明中，术语“多个”独立指2、3、4、5个。In the present invention, the term "plurality" means 2, 3, 4, 5 independently.
活性成分Active ingredient
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I'化合物、或其药学上可接受的盐、水合物、溶剂化物、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。As used herein, the terms "compounds of the present invention" or "active ingredients of the present invention" are used interchangeably and refer to compounds of formula I', or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds (such as deuterium Substitute compound) or prodrug. The term also includes racemates and optical isomers.
所述的式I'化合物具有如下结构：The compound of formula I'has the following structure:
Figure PCTCN2020091425-appb-000063
Figure PCTCN2020091425-appb-000063
R 1、X 3、W、Q1、X 5、X 6、R 2、R 3、R 4、A、m和n的定义如上所述，优选地W环为取代或未取代的下组基团：5-6元单环亚杂环基、8-10元双环亚杂环基或5-6元单环亚杂芳基或8-10元双环亚杂芳基；所述取代是指任选地被0-2个R 5取代；R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氧代基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基；更优选地，W环选自：
Figure PCTCN2020091425-appb-000064
Figure PCTCN2020091425-appb-000065
其中，X 1、X 2、X 7、X 8、Q2的定义如上所述，且X 7、X 8中至少有一个为N。 The definitions of R 1 , X 3 , W, Q1, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are as described above, and the ring W is preferably a substituted or unsubstituted group ：5-6 membered monocyclic heterocyclylene, 8-10 membered bicyclic heterocyclylene or 5-6 membered monocyclic heteroarylene or 8-10 membered bicyclic heteroarylene; said substitution means optional Ground is substituted by 0-2 R 5 ; R 5 is each independently selected from: hydrogen, C1～C6 alkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 alkoxy, C1～C6 alkane Amino, halogen, C1-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclic, heterocycloalkyl, nitro, oxo, cyano, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S (O) 2 -N(R 6 )(R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C (O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S (O) 2 R 7 and -P(O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl group, heteroaryl group, aryloxy group, aralkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0 to 5 R a; R a optionally from: C1 ~ C6 alkyl group, halo, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano; more preferably, the W ring is selected from:
Figure PCTCN2020091425-appb-000064
Figure PCTCN2020091425-appb-000065
Wherein, X 1 , X 2 , X 7 , X 8 , and Q2 are defined as described above, and at least one of X 7 and X 8 is N.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(Ⅱ)、式(Ⅲ)或式(Ⅳ)所示的结构Preferably, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula (II), formula (III) or formula (IV)
Figure PCTCN2020091425-appb-000066
Figure PCTCN2020091425-appb-000066
其中，R 1、X 1、X 2、X 3、Q1、Q2、X 5、X 6、R 2、R 3、R 4、A、m和n的定义如上所述。 Wherein, R 1 , X 1 , X 2 , X 3 , Q1, Q2, X 5 , X 6 , R 2 , R 3 , R 4 , A, m and n are as defined above.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(2)、式(3)或式(4)所示的结构Preferably, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula (2), formula (3) or formula (4)
Figure PCTCN2020091425-appb-000067
Figure PCTCN2020091425-appb-000067
Figure PCTCN2020091425-appb-000068
Figure PCTCN2020091425-appb-000068
其中，R 1、X 1、X 2、Q1、Q2、R 2、R 3、R 4、A和m的定义如上所述。 Wherein, R 1 , X 1 , X 2 , Q1, Q2, R 2 , R 3 , R 4 , A and m are as defined above.
优选地，上述化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式2'所示的结构Preferably, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2'
Figure PCTCN2020091425-appb-000069
Figure PCTCN2020091425-appb-000069
其中，
Figure PCTCN2020091425-appb-000070
为单键或双键； among them,
Figure PCTCN2020091425-appb-000070
Single bond or double bond;
X 1、X 2、R 1、R 2、R 3、R 4、A、R 17、f和m的定义如上所述。 X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , A, R 17 , f, and m are defined as described above.
优选地，上述化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式2”所示的结构Preferably, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2"
Figure PCTCN2020091425-appb-000071
Figure PCTCN2020091425-appb-000071
其中，among them,
X 1、X 2、R 1、R 2、R 3、R 4、A、m和R 17的定义如上所述。 X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , A, m and R 17 are as defined above.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式3'所示的结构Preferably, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3'
Figure PCTCN2020091425-appb-000072
Figure PCTCN2020091425-appb-000072
其中，
Figure PCTCN2020091425-appb-000073
为单键或双键； among them,
Figure PCTCN2020091425-appb-000073
Single bond or double bond;
Figure PCTCN2020091425-appb-000074
为单键时，Y 4选自：N或CR 17，
Figure PCTCN2020091425-appb-000074
When it is a single bond, Y 4 is selected from: N or CR 17 ,
Figure PCTCN2020091425-appb-000075
为双键时，Y 4为C；
Figure PCTCN2020091425-appb-000075
When it is a double bond, Y 4 is C;
R 1、X 2、R 2、R 3、R 4、R 17、A、m、f、p和Q2的定义如上所述。 R 1 , X 2 , R 2 , R 3 , R 4 , R 17 , A, m, f, p, and Q2 are as defined above.
在另一优选例中，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式3”所示的结构In another preferred embodiment, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3"
Figure PCTCN2020091425-appb-000076
Figure PCTCN2020091425-appb-000076
R 1、X 2、R 2、R 3、R 4、A、Q2、m和R 17的定义如上所述。 R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式4'所示的结构：Preferably, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4':
Figure PCTCN2020091425-appb-000077
Figure PCTCN2020091425-appb-000077
其中，
Figure PCTCN2020091425-appb-000078
为单键或双键； among them,
Figure PCTCN2020091425-appb-000078
Single bond or double bond;
Figure PCTCN2020091425-appb-000079
为单键时，Y 4选自：N或CR 17；
Figure PCTCN2020091425-appb-000079
When it is a single bond, Y 4 is selected from: N or CR 17 ;
Figure PCTCN2020091425-appb-000080
为双键时，Y 4为C；
Figure PCTCN2020091425-appb-000080
When it is a double bond, Y 4 is C;
R 1、X 2、R 2、R 3、R 4、R 17、A、m、f、p和Q2的定义如上所述。 R 1 , X 2 , R 2 , R 3 , R 4 , R 17 , A, m, f, p, and Q2 are as defined above.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式4”所示的结构，Preferably, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4",
Figure PCTCN2020091425-appb-000081
Figure PCTCN2020091425-appb-000081
R 1、X 2、R 2、R 3、R 4、A、Q2、m和R 17的定义如上所述。 R 1 , X 2 , R 2 , R 3 , R 4 , A, Q2, m, and R 17 are as defined above.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式5、式6所示的结构：Preferably, the compound of Formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in Formula 5 and Formula 6:
Figure PCTCN2020091425-appb-000082
Figure PCTCN2020091425-appb-000082
其中，R 1、X 7、X 8、X 2、Q2、R 2、R 3、R 4、R 17、A和m的定义如上所述，且X 7、X 8中至少有一个为N。 Wherein, R 1 , X 7 , X 8 , X 2 , Q2, R 2 , R 3 , R 4 , R 17 , A and m are as defined above, and at least one of X 7 and X 8 is N.
优选地，上述各式中，R 1任选自以下结构中的一种： Preferably, in the above formulas, R 1 is optionally selected from one of the following structures:
Figure PCTCN2020091425-appb-000083
Figure PCTCN2020091425-appb-000083
Figure PCTCN2020091425-appb-000084
Figure PCTCN2020091425-appb-000084
Figure PCTCN2020091425-appb-000085
更优选地R 1为
Figure PCTCN2020091425-appb-000086
Figure PCTCN2020091425-appb-000085
More preferably R 1 is
Figure PCTCN2020091425-appb-000086
R 2任选自氢、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl The group is optionally and independently substituted with 0-5 Ra ;
R a任选自C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、环烷基、杂环烷基或氰基。 R a optionally from C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano.
优选地，上述各式中，W环选自：
Figure PCTCN2020091425-appb-000087
Figure PCTCN2020091425-appb-000088
其中， Preferably, in the above formulas, the W ring is selected from:
Figure PCTCN2020091425-appb-000087
Figure PCTCN2020091425-appb-000088
among them,
Figure PCTCN2020091425-appb-000089
选自：
Figure PCTCN2020091425-appb-000090
Figure PCTCN2020091425-appb-000089
Selected from:
Figure PCTCN2020091425-appb-000090
Figure PCTCN2020091425-appb-000091
选自：
Figure PCTCN2020091425-appb-000092
Figure PCTCN2020091425-appb-000093
Figure PCTCN2020091425-appb-000094
Figure PCTCN2020091425-appb-000095
优选地
Figure PCTCN2020091425-appb-000096
选自：
Figure PCTCN2020091425-appb-000097
Figure PCTCN2020091425-appb-000098
Figure PCTCN2020091425-appb-000091
Selected from:
Figure PCTCN2020091425-appb-000092
Figure PCTCN2020091425-appb-000093
Figure PCTCN2020091425-appb-000094
Figure PCTCN2020091425-appb-000095
Preferably
Figure PCTCN2020091425-appb-000096
Selected from:
Figure PCTCN2020091425-appb-000097
Figure PCTCN2020091425-appb-000098
Figure PCTCN2020091425-appb-000099
部分选自：
Figure PCTCN2020091425-appb-000100
Figure PCTCN2020091425-appb-000101
Figure PCTCN2020091425-appb-000099
Partly selected from:
Figure PCTCN2020091425-appb-000100
Figure PCTCN2020091425-appb-000101
其中，
Figure PCTCN2020091425-appb-000102
为单键或双键； among them,
Figure PCTCN2020091425-appb-000102
Single bond or double bond;
R 12独立地选自：H、卤素、C1～C6烷基、C1～C6烷氧基、硝基、氰基、氨基； R 12 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, amino;
各Y 1、Y 2、Y 3独立地选自：O、N、NR 17、CR 13、CR 13R 14； Each of Y 1, Y 2, Y 3 is independently selected from: O, N, NR 17 , CR 13 , CR 13 R 14 ;
R 13、R 14、R 15、R 16各自独立地选自：H、卤素、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、硝基、氰基、氨基；或者R 13和R 14与其连接的C原子一起形成羰基(C＝O)；或者R 15和R 16与其连接的C原子一起形成羰基(C＝O)； R 13 , R 14 , R 15 , and R 16 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, amino; or R 13 and R 14 together with the C atom to which they are connected form a carbonyl group (C=O); or R 15 and R 16 together with the C atom to which they are connected form a carbonyl group (C=O);
R 17选自：H、C1～C6烷基。 R 17 is selected from: H, C1-C6 alkyl.
优选地，上述各式中，A为芳香环、杂芳环，更优选地，A为苯基、吡啶基、吡嗪基、嘧啶基或哒嗪基；所述杂芳环含有0～3个杂原子，杂原子任选自N、O、S；A环上的任意氢原子可被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基。Preferably, in the above formulas, A is an aromatic ring or a heteroaromatic ring. More preferably, A is a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a pyridazinyl group; the heteroaromatic ring contains 0 to 3 Heteroatoms, heteroatoms can be selected from N, O, S; any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～ C6 alkyl, C1～C6 haloalkyl, C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 ring Alkylamino, aryl or heteroaryl.
优选地，上述各式中，R 4各自独立地任选自：芳基、杂芳基、芳氧基、芳烷基、杂环基，更优选地R 4为5元杂芳基；其中，每个芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基；更优选地R 4选自：
Figure PCTCN2020091425-appb-000103
其中，R 18选自：卤素(优选地为F)、C1～C6烷基。 Preferably, in the above formulas, R 4 is independently selected from: aryl, heteroaryl, aryloxy, aralkyl, heterocyclic group, more preferably R 4 is a 5-membered heteroaryl group; wherein, each aryl, heteroaryl, aryloxy, arylalkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0 to 5 R a; R a optionally from: C1 ~ C6 alkyl group, halo , Hydroxyl, C1～C6 heteroalkyl, C1～C6 alkoxy, C1～C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano; more preferably R 4 is selected from:
Figure PCTCN2020091425-appb-000103
Wherein, R 18 is selected from: halogen (preferably F), C1-C6 alkyl.
优选地，上述各式中，m为1。Preferably, in the above formulas, m is 1.
优选地，上述各式中，R 3为H、C1-C6烷基、C1-C6烷氧基。 Preferably, in the above formulas, R 3 is H, C1-C6 alkyl, or C1-C6 alkoxy.
优选地，上述各式中，R 2为H。 Preferably, in the above formulas, R 2 is H.
优选地，上述各式中，
Figure PCTCN2020091425-appb-000104
部分为
Figure PCTCN2020091425-appb-000105
其中，X 9、X 10各自独立地选自N或CR 5，其中，R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、硝基、氰基、氨基；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基各自独立地被0～5个R a取代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基。 Preferably, in the above formulas,
Figure PCTCN2020091425-appb-000104
Partly
Figure PCTCN2020091425-appb-000105
Wherein, X 9 and X 10 are each independently selected from N or CR 5 , wherein each of R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, C1～C6 alkylamino, halogen, C1～C6 heteroalkyl, cycloalkyl, nitro, cyano, amino; wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkane amino, heteroalkyl, cycloalkyl independently substituted with 0 to 5 R a; R a optionally from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy Group, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl or cyano.
优选地，式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式5'或6'所示的结构Preferably, the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5'or 6'
Figure PCTCN2020091425-appb-000106
Figure PCTCN2020091425-appb-000106
Figure PCTCN2020091425-appb-000107
Figure PCTCN2020091425-appb-000107
X 2、X 7、X 8、X 9、X 10和Q2环的定义如上所述，且X 7、X 8中至少有一个为N。 The definitions of X 2 , X 7 , X 8 , X 9 , X 10 and Q2 ring are as described above, and at least one of X 7 and X 8 is N.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I'与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。The salts that the compounds of the present invention may form also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts. The term "salt" as used herein refers to a salt in the acid or basic form formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion ("internal salt") that may be formed is contained in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process. The compound of the present invention may form a salt. For example, the compound I'can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or freeze-dried in an aqueous solution.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate. , Benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。The acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed by organic bases (such as organic amines), such as benzathine and dicyclohexylamine , Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfate (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化 合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。The prodrugs and solvates of the compounds of the present invention are also covered. The term "prodrug" herein refers to a compound that undergoes metabolism or chemical transformation through a chemical process to produce the compound, salt, or solvate of the present invention when treating related diseases. The compounds of the present invention include solvates such as hydrates.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention. The independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them. The chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and recrystallization.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。In the compound of the present invention, the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed. Here, such "very pure" compounds of the invention are also part of the invention.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form. The definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。 Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. The definition of specific functional groups is also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and the entire contents are included in the reference list.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin the mixture and other mixtures. In addition, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。According to the present invention, the mixture of isomers can contain various isomer ratios. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those skilled in the art and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本 发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。 The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in fact, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different. Examples of isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds in the present invention, such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates. Tritium, namely 3 H and carbon-14, namely 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie 2 H, have advantages in certain therapies due to its good metabolic stability, such as increasing the half-life or reducing the dosage in the body, so it can be given priority in some cases. Isotopically-labeled compounds can be prepared by a general method, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If you want to design the synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. The pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention can be combined with any number of substituents or functional groups to expand their coverage. Generally, whether the term "substituted" appears before or after the term "optional", the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different. The term "substitution" as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence. In addition, the present invention is not intended to limit the permitted substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds. Here, the term "stable" refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds and their pharmaceutically acceptable salts involved in the application, as well as the prodrugs that can be transformed into the structure of the compounds and their pharmaceutically acceptable salts involved in the application, are also included in the claims of the application. in.
制备方法Preparation
以下方案和实例中描述了制备式I'的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。The method for preparing the compound of formula I'is described in the following schemes and examples. Raw materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise specified. In some cases, the order of steps in the implementation of the reaction scheme can be changed to promote the reaction or avoid unwanted side reaction products.
下面更具体地描述本发明式I'结构化合物的制备方法，但这些具体方法不对本发明构 成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。The preparation methods of the compound of formula I'of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
通常，在制备流程中，各反应通常惰性气体保护下，适当溶剂中，在0到90℃下进行，反应时间通常为2-24小时。Generally, in the preparation process, each reaction is usually carried out at 0 to 90° C. under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.
优选地制备方法如下：The preferred preparation method is as follows:
方法一：method one:
Figure PCTCN2020091425-appb-000108
Figure PCTCN2020091425-appb-000108
第一步：在溶剂(如DMF/H 2O、二氧六环、甲苯)中，碱性(如碳酸钾、碳酸钠等)条件下，催化剂和配体(如Pd(PPh 3) 4)存在下，
Figure PCTCN2020091425-appb-000109
反应，得到
Figure PCTCN2020091425-appb-000110
The first step: in a solvent (such as DMF/H 2 O, dioxane, toluene), under alkaline (such as potassium carbonate, sodium carbonate, etc.) conditions, catalyst and ligand (such as Pd(PPh 3 ) 4 ) Exist,
Figure PCTCN2020091425-appb-000109
Response, get
Figure PCTCN2020091425-appb-000110
第二步：在惰性溶剂(如DMF、二氧六环、乙二醇二甲醚等)中，碱性(如二异丙基乙胺、乙酸钾、DBU等)条件下或者是催化剂和配体(如Pd(PPh 3) 4、Pd 2(dba) 3\t-BuXphos等)存在下，
Figure PCTCN2020091425-appb-000111
与
Figure PCTCN2020091425-appb-000112
反应，得到
Figure PCTCN2020091425-appb-000113
The second step: in an inert solvent (such as DMF, dioxane, ethylene glycol dimethyl ether, etc.), under alkaline (such as diisopropylethylamine, potassium acetate, DBU, etc.) conditions or a catalyst and Body (such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 \t-BuXphos, etc.),
Figure PCTCN2020091425-appb-000111
versus
Figure PCTCN2020091425-appb-000112
Response, get
Figure PCTCN2020091425-appb-000113
第三步：在惰性溶剂(如DMF)中，缩合剂(如DMAP、HATU、PyBOP等)存 在下，
Figure PCTCN2020091425-appb-000114
与
Figure PCTCN2020091425-appb-000115
反应，得到式I'。 The third step: in the presence of an inert solvent (such as DMF) and a condensing agent (such as DMAP, HATU, PyBOP, etc.),
Figure PCTCN2020091425-appb-000114
versus
Figure PCTCN2020091425-appb-000115
Reaction to obtain formula I'.
方法二Method Two
Figure PCTCN2020091425-appb-000116
Figure PCTCN2020091425-appb-000116
第一步：在惰性溶剂(如DMF、二氧六环、乙二醇二甲醚等)中，碱性(如二异丙基乙胺、乙酸钾、DBU等)条件下或者是催化剂和配体(如Pd(PPh 3) 4、Pd 2(dba) 3\t-BuXphos等)存在下，
Figure PCTCN2020091425-appb-000117
与
Figure PCTCN2020091425-appb-000118
反应，得到
Figure PCTCN2020091425-appb-000119
The first step: in an inert solvent (such as DMF, dioxane, ethylene glycol dimethyl ether, etc.), under alkaline (such as diisopropylethylamine, potassium acetate, DBU, etc.) conditions or a catalyst and Body (such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 \t-BuXphos, etc.),
Figure PCTCN2020091425-appb-000117
versus
Figure PCTCN2020091425-appb-000118
Response, get
Figure PCTCN2020091425-appb-000119
第二步：在惰性溶剂(如DMF/H 2O)中，碱性(如K 2CO 3)条件下，催化剂和配体(如Pd(PPh 3) 4)存在下，
Figure PCTCN2020091425-appb-000120
反应，得到
Figure PCTCN2020091425-appb-000121
Step 2: In an inert solvent (such as DMF/H 2 O), under alkaline (such as K 2 CO 3 ) conditions, in the presence of catalysts and ligands (such as Pd(PPh 3 ) 4 ),
Figure PCTCN2020091425-appb-000120
Response, get
Figure PCTCN2020091425-appb-000121
第三步，在惰性溶剂(如DMF)中，缩合剂(如DMAP、HATU、PyBOP等)存在下，
Figure PCTCN2020091425-appb-000122
与
Figure PCTCN2020091425-appb-000123
反应，得到式I'。 In the third step, in the presence of a condensing agent (such as DMAP, HATU, PyBOP, etc.) in an inert solvent (such as DMF),
Figure PCTCN2020091425-appb-000122
versus
Figure PCTCN2020091425-appb-000123
Reaction to obtain formula I'.
上述各式中，G、G'各自独立地为卤素(如F、Cl、Br)；In the above formulas, G and G'are each independently a halogen (such as F, Cl, Br);
G”为硼酸酯基(如
Figure PCTCN2020091425-appb-000124
)； G" is a borate group (such as
Figure PCTCN2020091425-appb-000124
);
X 3'选自：OH、-NHR 8、-CHR 9R 10、
Figure PCTCN2020091425-appb-000125
X 3 'is selected from: OH, -NHR 8 , -CHR 9 R 10 ,
Figure PCTCN2020091425-appb-000125
X 5'选自：-C(O)-OH、-S(O)-OH、-S(O) 2-OH、
Figure PCTCN2020091425-appb-000126
X 5 'is selected from: -C(O)-OH, -S(O)-OH, -S(O) 2 -OH,
Figure PCTCN2020091425-appb-000126
R 1、X 3、W、Q1、X 5、X 6、R 2、R 3、R 4、A、Q2、m和n的定义如上所述。 The definitions of R 1 , X 3 , W, Q1, X 5 , X 6 , R 2 , R 3 , R 4 , A, Q2, m and n are as described above.
如无特别说明，上述起始原料均可通过商业途径购买或按照已报道的文献合成。Unless otherwise specified, the above-mentioned starting materials can be purchased commercially or synthesized according to reported literature.
药物组合物和施用方法Pharmaceutical composition and method of administration
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。The pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
通式I'所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I'的化合物。当式I'化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I'化合物的药用组合物。药物联用也包括在重叠的时间段服用式I'化合物与其它一种或几种已知药物。当式I'化合物与其它一种或几种药物进行药物联用时，式I'化合物或已知药物的剂量可能比它们单独用药的剂量低。The compound of formula I'can be combined with other drugs known to treat or improve similar conditions. In the case of combined administration, the original drug administration mode and dosage can remain unchanged, while the compound of formula I'is administered simultaneously or subsequently. When the compound of formula I'is administered with one or more other drugs at the same time, a pharmaceutical composition containing one or more known drugs and the compound of formula I'can be preferably used. The combination of drugs also includes taking the compound of formula I'and one or more other known drugs in overlapping time periods. When the compound of formula I'is used in combination with one or more other drugs, the dose of the compound of formula I'or the known drug may be lower than the dose of the compound used alone.
可以与通式I'所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。The drugs or active ingredients that can be used in combination with the compound of formula I'include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB -A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biological analogues of the above drugs, etc.), PD-L1 inhibitors (such as devaluzumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituo Coximab, obin utuzumab, ofatumumab, tositumomab, ibimumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI- 622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lolatin Ni, okatinib), PI3K inhibitors (such as Aidelaris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as Afatinib) Ni, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, Swiss Vatinib, Cabozantinib, Sunitinib, Donafinib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinotide, Daxilast, Tecdinaline, etc.), CDK inhibitors (E.g. Pabocinib, Reboscine, Abemaciclib, Lerociclib, etc.), MEK inhibitors (e.g. Simetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI -1040) etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) , IGF-1R inhibitors (such as Ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.) or combinations thereof.
本发明药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。The dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano formulation.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020091425-appb-000127
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween)
Figure PCTCN2020091425-appb-000127
), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油 和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。The dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。The treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered. For a 60kg body weight, the daily The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式I'化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。The present invention also provides a method for preparing a pharmaceutical composition, which comprises the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula I'or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention The compound is mixed to form a pharmaceutical composition.
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述式I'化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于抑制RET。The present invention also provides a treatment method, which comprises the steps of: administering the compound of formula I'in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, to a subject in need of treatment, or Administration of the pharmaceutical composition of the present invention is used to inhibit RET.
本发明具有以下主要优点：The present invention has the following main advantages:
(1)本发明化合物对RET激酶具有优良的抑制能力；(1) The compound of the present invention has excellent inhibitory ability on RET kinase;
(2)本发明化合物具有更低的毒副作用；(2) The compound of the present invention has lower toxic and side effects;
(3)本发明化合物更好的药效学、药代动力学性能。(3) The compound of the present invention has better pharmacodynamics and pharmacokinetic properties.
实施例Example
下面对本发明的技术方案作进一步的说明，但本发明的保护范围不限于此。The technical solution of the present invention will be further described below, but the protection scope of the present invention is not limited to this.
实施例1Example 1
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000128
Figure PCTCN2020091425-appb-000128
Figure PCTCN2020091425-appb-000129
Figure PCTCN2020091425-appb-000129
实验过程如下：The experiment process is as follows:
一、中间体C1-7的合成1. Synthesis of Intermediate C1-7
合成路线如下：The synthetic route is as follows:
Figure PCTCN2020091425-appb-000130
Figure PCTCN2020091425-appb-000130
1、C1-9的合成1. Synthesis of C1-9
于100mL单口瓶中加入C1-8(6.98g，34.9mmol)、4-氟-1H-吡唑(3.3g，35mmol)、碳酸钾(11.1g，73.6mmol)和DMF(30mL)，于100℃反应15h，冷却到室温，倒入水中，过滤，干燥得5.93g化合物C1-9。化合物C1-9的核磁分析数据： 1H NMR(400MHz,CDCl 3)：δ8.96-8.95(d,J＝1.8Hz,1H),8.47-8.45(dd,1H),8.37-8.34(dd,1H),8.05-8.03(dd,1H),7.66-7.65(d,J＝3.96,1H),2.65(s,3H)。 Add C1-8 (6.98g, 34.9mmol), 4-fluoro-1H-pyrazole (3.3g, 35mmol), potassium carbonate (11.1g, 73.6mmol) and DMF (30mL) into a 100mL single-necked flask. React for 15 hours, cool to room temperature, pour into water, filter, and dry to obtain 5.93 g of compound C1-9. NMR analysis data of compound C1-9: 1 H NMR (400MHz, CDCl 3 ): δ8.96-8.95 (d, J = 1.8Hz, 1H), 8.47-8.45 (dd, 1H), 8.37-8.34 (dd, 1H), 8.05-8.03 (dd, 1H), 7.66-7.65 (d, J=3.96, 1H), 2.65 (s, 3H).
2、C1-10的合成2. Synthesis of C1-10
于100mL三口瓶中加入C1-9(4.2g，0.02mol)、R-叔丁基亚磺酰胺(2.48g，0.02mol)、钛酸四乙酯(9.34g，0.041mol)和THF(50mL)，于75℃反应15h，冷却到室温，倒入水中，过滤，滤饼用乙酸乙酯洗涤，合并有机相，干燥浓缩柱层析得5.35g化合物C1-10。Add C1-9 (4.2g, 0.02mol), R-tert-butylsulfinamide (2.48g, 0.02mol), tetraethyl titanate (9.34g, 0.041mol) and THF (50mL) into a 100mL three-necked flask , React at 75°C for 15h, cool to room temperature, pour into water, filter, wash the filter cake with ethyl acetate, combine the organic phases, dry and concentrate the column chromatography to obtain 5.35g of compound C1-10.
化合物C1-10的核磁分析数据： 1H NMR(400MHz,CDCl 3)：δ8.96-8.95(d,J＝1.8Hz,1H),8.47-8.45(dd,1H),8.37-8.34(dd,1H),8.05-8.03(dd,1H),7.66-7.65(d,J＝3.96,1H),2.65(s,3H)。 NMR analysis data of compound C1-10: 1 H NMR (400MHz, CDCl 3 ): δ8.96-8.95 (d, J = 1.8Hz, 1H), 8.47-8.45 (dd, 1H), 8.37-8.34 (dd, 1H), 8.05-8.03 (dd, 1H), 7.66-7.65 (d, J=3.96, 1H), 2.65 (s, 3H).
3、C1-11的合成3. Synthesis of C1-11
于100mL三口瓶中加入C1-10(3.5g)和THF(50mL)，降温到零下70℃，滴加三仲丁基硼氢化锂的THF溶液(1M，34.1mL)，于该温度下搅拌半小时，自然升温 到室温，TLC显示反应完全，加入5mL甲醇淬灭反应，再加入水，过滤，滤饼用乙酸乙酯洗涤。合并有机相，干燥浓缩，柱层析得3.1g化合物C1-11。化合物C1-11的核磁分析数据： 1H NMR(400MHz,CDCl 3)：δ8.40-8.39(d,J＝4.6Hz,1H),8.36-8.35(d,J＝2.08Hz,1H),7.94-7.91(d,J＝8.48Hz,1H),7.79-7.76(m,1H),7.59-7.58(d,J＝4.28,1H),4.68-4.63(m,1H),3.37-3.36(m,1H),1.59-1.57(d,J＝6.72,3H),1.21(s,9H)。 C1-10 (3.5g) and THF (50mL) were added to a 100mL three-necked flask, the temperature was reduced to minus 70°C, and a THF solution (1M, 34.1mL) of lithium tri-sec-butylborohydride (1M, 34.1mL) was added dropwise, and stirred at this temperature for half After hours, the temperature was naturally warmed to room temperature, TLC showed that the reaction was complete, 5 mL of methanol was added to quench the reaction, water was added, filtered, and the filter cake was washed with ethyl acetate. The organic phases were combined, dried and concentrated, and column chromatography was used to obtain 3.1 g of compound C1-11. NMR analysis data of compound C1-11: 1 H NMR (400MHz, CDCl 3 ): δ8.40-8.39 (d, J=4.6Hz, 1H), 8.36-8.35 (d, J=2.08Hz, 1H), 7.94 -7.91(d,J=8.48Hz,1H), 7.79-7.76(m,1H), 7.59-7.58(d,J=4.28,1H), 4.68-4.63(m,1H), 3.37-3.36(m, 1H), 1.59-1.57 (d, J = 6.72, 3H), 1.21 (s, 9H).
4、C1-7的合成4. Synthesis of C1-7
于100mL三口瓶中加入C1-11(3.1g)，加入甲醇(10mL)，1,4-二氧六环(10mL)，搅拌使其溶解后，加入HCl/1,4-二氧六环(4M,25mL)，室温搅拌2h，浓缩反应液得粗品，将粗品在***中打浆得2.27g化合物C1-7。Add C1-11 (3.1g) into a 100mL three-necked flask, add methanol (10mL), 1,4-dioxane (10mL), stir to dissolve, add HCl/1,4-dioxane ( 4M, 25mL), stirred at room temperature for 2h, concentrated the reaction solution to obtain a crude product, and slurried the crude product in ether to obtain 2.27g of compound C1-7.
化合物C1-7的核磁分析数据： 1H NMR(400MHz,DMSO-D 6)：δ8.79(br,3H),8.74-8.72(m,1H),8.64-8.63(d,J＝2.08Hz,1H),8.23-8.20(m,1H),7.97-7.95(m,2H),4.52-4.52(m,1H),1.60-1.58(d,J＝6.84Hz,3H)。 NMR analysis data of compound C1-7: 1 H NMR (400MHz, DMSO-D 6 ): δ8.79 (br, 3H), 8.74-8.72 (m, 1H), 8.64-8.63 (d, J=2.08 Hz, 1H), 8.23-8.20 (m, 1H), 7.97-7.95 (m, 2H), 4.52-4.52 (m, 1H), 1.60-1.58 (d, J = 6.84 Hz, 3H).
二、中间体C1-3的合成2. Synthesis of Intermediate C1-3
合成路线如下：The synthetic route is as follows:
Figure PCTCN2020091425-appb-000131
1、化合物C1-13的合成
Figure PCTCN2020091425-appb-000131
1. Synthesis of compound C1-13
250mL三口瓶中，加入溴仿(125mL)和C1-12(128mmol,20g)，搅拌溶解，冷却至0℃，缓慢滴加KOH(1mol,57.4g)的甲醇(300mL)溶液。滴加完毕，升至室温搅拌16h。TLC显示反应完全，浓缩母液，加水(50mL)稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到产品25g C1-13，直接用于下一步。In a 250mL three-neck flask, add bromoform (125mL) and C1-12 (128mmol, 20g), stir to dissolve, cool to 0°C, and slowly add a solution of KOH (1mol, 57.4g) in methanol (300mL) dropwise. After the addition was completed, the temperature was raised to room temperature and stirred for 16 hours. TLC showed that the reaction was complete, the mother liquor was concentrated, diluted with water (50 mL), extracted with ethyl acetate three times, the organic phase was washed with saturated brine, the organic phase was dried, and concentrated under reduced pressure to obtain the product 25g C1-13, which was used directly in the next step.
2、化合物C1-14的合成2. Synthesis of compound C1-14
500mL单口瓶中，加入C1-13(86mmol,20g)和甲醇(200mL)，常温搅拌下加入浓盐酸(100mL)，室温搅拌16h，TLC显示反应完全，浓缩母液，加入饱和NaHCO 3水溶液调pH＝6-7，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得粗品，柱层析纯化(展开剂：乙酸乙酯/石油醚＝1:30-1:5)得到产品10g C1-14。 Add C1-13 (86mmol, 20g) and methanol (200mL) to a 500mL single-mouth flask, add concentrated hydrochloric acid (100mL) under stirring at room temperature, stir at room temperature for 16h, TLC shows the reaction is complete, concentrate the mother liquor, add saturated NaHCO 3 aqueous solution to adjust the pH= 6-7, ethyl acetate extraction three times, the organic phase was washed with saturated brine, the organic phase was dried, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (developing solvent: ethyl acetate/petroleum ether=1:30-1:5) The product 10g C1-14 was obtained.
3、化合物C1-15的合成3. Synthesis of compound C1-15
250mL三口瓶中，加入无水甲苯50mL和无水吡啶(4.5mL,53mmol)，冷却至-10℃。氮气保护下，缓慢滴加三氟甲磺酸酐(10.8mL,60mmol)的无水甲苯(60mL)溶液。滴加完毕，缓慢升至室温，加入C1-14(9g,48mmol)的无水甲苯(30mL)溶液。反应液升至40℃，搅拌16h。TLC显示反应完全，加水10ml稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，柱层析纯化(展 开剂：乙酸乙酯/石油醚＝1:40-1:20)得到产品9g C1-15。Add 50 mL of anhydrous toluene and anhydrous pyridine (4.5 mL, 53 mmol) to a 250 mL three-necked flask, and cool to -10°C. Under the protection of nitrogen, a solution of trifluoromethanesulfonic anhydride (10.8 mL, 60 mmol) in dry toluene (60 mL) was slowly added dropwise. After the addition is complete, slowly warm to room temperature, and add a solution of C1-14 (9g, 48mmol) in anhydrous toluene (30mL). The reaction solution was raised to 40°C and stirred for 16h. TLC showed that the reaction was complete, diluted with water 10ml, extracted three times with ethyl acetate, washed the organic phase with saturated brine, dried the organic phase, concentrated under reduced pressure to obtain the crude product, purified by column chromatography (developing solvent: ethyl acetate/petroleum ether = 1:40 -1:20) 9g of product C1-15 is obtained.
4、化合物C1-3的合成4. Synthesis of compound C1-3
氮气保护下，于250mL三口瓶中，依次加入C1-15(9g,28mmol),双联频哪醇硼酸酯(8.7g,34mmol)、dppf(1.5g,3mmol)、醋酸钯(350mg,1.5mmol)、醋酸钾(8.25g,88mmol)和二氧六环(120mL)，氮气置换三次，然后反应液在95℃搅拌16小时，TLC显示反应完全，过滤后减压浓缩，然后加水20mL稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，柱层析纯化(展开剂：乙酸乙酯/石油醚＝1:20-1:10)得到产品C1-3(淡黄固体，8g)。Under the protection of nitrogen, in a 250mL three-necked flask, add C1-15 (9g, 28mmol), double pinacol borate (8.7g, 34mmol), dppf (1.5g, 3mmol), palladium acetate (350mg, 1.5 mmol), potassium acetate (8.25g, 88mmol) and dioxane (120mL), replaced with nitrogen three times, then the reaction solution was stirred at 95°C for 16 hours, TLC showed that the reaction was complete, filtered and concentrated under reduced pressure, and then diluted with 20mL of water. The organic phase was extracted three times with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was dried, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (developing solvent: ethyl acetate/petroleum ether = 1:20-1:10) to obtain product C1- 3 (Light yellow solid, 8g).
三、化合物C1，C2的合成3. Synthesis of compound C1, C2
合成路线如下：The synthetic route is as follows:
Figure PCTCN2020091425-appb-000132
Figure PCTCN2020091425-appb-000132
1、C1-2的合成1. Synthesis of C1-2
于250mL单口瓶中加入C1-1(3.46g，20mmol)、3-氨基-5-甲基吡唑(2.14g，22mmol)、DMF(50mL)、二异丙基乙胺(3.88g，30mmol)，将反应置于90℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入200mL水中有固体析出，过滤，水洗滤饼，将滤饼干燥，后用甲醇(100mL)打浆，过滤，重复操作3-5次，得2.82g。[M+H]:234.1。Add C1-1 (3.46g, 20mmol), 3-amino-5-methylpyrazole (2.14g, 22mmol), DMF (50mL), and diisopropylethylamine (3.88g, 30mmol) into a 250mL single-mouth flask , The reaction was placed at 90°C overnight. LC-MS showed that the reaction was complete. Pour the reaction solution into 200 mL of water with stirring, and solids precipitated. Filter, wash the filter cake with water, dry the filter cake, then beaten with methanol (100 mL), filter, repeat the operation 3-5 times to obtain 2.82 g. [M+H]: 234.1.
2、C1-4的合成2. Synthesis of C1-4
于250mL单口瓶中加入C1-2(2.1g，9mmol)、C1-3(2.66g，9mmol)，Pd(PPh 3) 4(1.04g，0.9mmol)、K 2CO 3(1.86g，13.5mmol)、DMF/H 2O(30mL/12mL)，N 2保护下将反应置于110℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入水(300mL)中，乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，旋干，柱层析DCM:MeOH＝50:1-10:1，得1.87g。[M+H]:368.2。 Add C1-2 (2.1g, 9mmol), C1-3 (2.66g, 9mmol), Pd(PPh 3 ) 4 (1.04g, 0.9mmol), K 2 CO 3 (1.86g, 13.5mmol) into a 250mL single-mouth flask ), DMF/H 2 O (30 mL/12 mL), and the reaction was placed at 110° C. overnight under the protection of N 2 . LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (300 mL), extracted with ethyl acetate 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, column chromatography DCM:MeOH=50:1 -10:1, get 1.87g. [M+H]: 368.2.
3、C1-5的合成3. Synthesis of C1-5
于250mL单口瓶中加入C1-4(720mg，1.96mmol)、Pd(OH) 2/C(10％，300mg)、EtOH(100mL)，H 2氛围下将反应置于80℃下反应过夜。LC-MS显示反应完 毕，过滤，旋干，柱层析DCM:MeOH＝100:1-50:1，得白色固体502mg。[M+H]:370.3。 C1-4 (720 mg, 1.96 mmol), Pd(OH) 2 /C (10%, 300 mg), EtOH (100 mL) were added to a 250 mL single-necked flask, and the reaction was placed at 80° C. overnight under H 2 atmosphere. LC-MS showed that the reaction was complete, filtered and spin-dried, column chromatography DCM:MeOH=100:1-50:1, to obtain 502 mg of white solid. [M+H]: 370.3.
4、C1-6的合成4. Synthesis of C1-6
于25mL单口瓶中加入C1-5(240mg，0.65mmol)、LiOH·H 2O(55mg，1.3mmol)、MeOH/H 2O(5mL/1mL)，将反应置于50℃下反应过夜。LC-MS显示反应完毕，-浓缩得粗品241mg。[M+H]:356.2。 C1-5 (240 mg, 0.65 mmol), LiOH·H 2 O (55 mg, 1.3 mmol), MeOH/H 2 O (5 mL/1 mL) were added to a 25 mL single-mouth flask, and the reaction was placed at 50° C. overnight. LC-MS showed that the reaction was complete, and the crude product was concentrated to obtain 241 mg. [M+H]: 356.2.
5、C1和C2的合成5. Synthesis of C1 and C2
于25mL单口瓶中加入C1-6(249mg，0.69mmol)、C1-7(212mg，0.76mmol)、DMF(2mL)，室温搅拌下加入DMAP(337mg，2.76mmol)、HATU(393mg，1.04mmol)将反应置于25℃下反应1h。LC-MS显示反应完毕，将反应液倒入水(20mL)中，乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，旋干，柱层析DCM:MeOH＝100:1-30:1，得粗品后制备分离得C2(12mg，purity：96.7％)；[M+H]:544.3；C1(11mg；purity：97.6％)，[M+H]:544.3。Add C1-6 (249mg, 0.69mmol), C1-7 (212mg, 0.76mmol), DMF (2mL) into a 25mL single-mouth flask, add DMAP (337mg, 2.76mmol), HATU (393mg, 1.04mmol) while stirring at room temperature The reaction was placed at 25°C for 1 h. LC-MS showed that the reaction was complete, the reaction solution was poured into water (20mL), extracted with ethyl acetate 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, column chromatography DCM:MeOH=100:1-30 1: After obtaining the crude product, C2 (12mg, purity: 96.7%) was prepared and separated; [M+H]: 544.3; C1 (11mg; purity: 97.6%), [M+H]: 544.3.
C1和C2的分离由waters高效液相色谱仪分离，制备分离的条件如下：The separation of C1 and C2 is separated by waters high performance liquid chromatograph. The conditions of preparation and separation are as follows:
仪器：watersInstrument: waters
色谱柱：innovalODS-2/C18(30×100mm,5μm)Column: innovativeODS-2/C18 (30×100mm,5μm)
流动相：A相：水(含0.1％三氟乙酸)Mobile phase: Phase A: water (containing 0.1% trifluoroacetic acid)
B相：甲醇Phase B: Methanol
流速：15.0ml/min，检测波长：254nmFlow rate: 15.0ml/min, detection wavelength: 254nm
溶剂：甲醇-水(1︰1)Solvent: methanol-water (1:1)
进样浓度：约15mg/mlInjection concentration: about 15mg/ml
进样量：2mlInjection volume: 2ml
出峰时间：14.7minPeak time: 14.7min
梯度程序：Gradient program:
Figure PCTCN2020091425-appb-000133
Figure PCTCN2020091425-appb-000133
实施例2Example 2
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000134
Figure PCTCN2020091425-appb-000134
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000135
Figure PCTCN2020091425-appb-000135
1、C3-2的合成1. Synthesis of C3-2
于100mL单口瓶加入氢溴酸的醋酸溶液31mL，在搅拌下，将5g化合物C3-1分批加入到该溶液中，控制温度不超过30℃。加毕，于室温反应2h。冷却到0℃，加入30mL乙酸乙酯，过滤，滤饼用乙酸乙酯洗涤。将滤饼加入到甲醇(50mL)中，搅拌，过滤，滤饼用甲醇(20mL)洗涤。将滤饼加入水中并搅拌，加入碳酸钠调节pH值到9，过滤，滤饼用水洗涤，干燥得4.7g化合物C3-2。31 mL of hydrobromic acid acetic acid solution was added to a 100 mL single-necked flask, and 5 g of compound C3-1 was added to the solution in batches with stirring, and the temperature was controlled not to exceed 30°C. After the addition, react at room temperature for 2h. Cool to 0°C, add 30 mL of ethyl acetate, filter, and wash the filter cake with ethyl acetate. The filter cake was added to methanol (50 mL), stirred, filtered, and the filter cake was washed with methanol (20 mL). The filter cake was added to water and stirred, sodium carbonate was added to adjust the pH to 9, filtered, the filter cake was washed with water, and dried to obtain 4.7 g of compound C3-2.
化合物C3-2的核磁分析数据： 1H NMR(400MHz,DMSO)：δ8.61-8.60(dd，1H),8.04-8.02(dd,1H),7.51-7.48(dd,1H),6.61(s,1H),6.49(br,2H)。 NMR analysis data of compound C3-2: 1 H NMR (400MHz, DMSO): δ8.61-8.60(dd,1H), 8.04-8.02(dd,1H),7.51-7.48(dd,1H), 6.61(s ,1H),6.49(br,2H).
2、C3-4的合成2. Synthesis of C3-4
于250mL三口瓶中加入C3-2(3g，0.013mol)、C1-3(4.56g,0.0154mol)、三环己基膦(0.36g，0.0013mol)、碳酸钾(2.7g，0.0195mol)、醋酸钯(146mg，0.65mmol)、二氧六环(60mL)和水(7mL)于100℃搅拌15h。冷却，过滤，浓缩，残留物加入水，二氯甲烷萃取，干燥，浓缩。残留物加入***，搅拌，过滤，滤饼干燥 得3g化合物C3-4。Add C3-2 (3g, 0.013mol), C1-3 (4.56g, 0.0154mol), tricyclohexylphosphine (0.36g, 0.0013mol), potassium carbonate (2.7g, 0.0195mol), acetic acid into a 250mL three-necked flask Palladium (146mg, 0.65mmol), dioxane (60mL) and water (7mL) were stirred at 100°C for 15h. Cool, filter, concentrate, add water to the residue, extract with dichloromethane, dry, and concentrate. The residue was added with ether, stirred, filtered, and the filter cake was dried to obtain 3 g of compound C3-4.
化合物C3-4的核磁分析数据： 1H NMR(400MHz,DMSO)：δ8.52-8.51(dd，1H),7.95-7.92(dd,1H),7.39-7.36(dd,1H),6.54-6.53(m,1H),6.49(s,H),6.03(br,2H),3.73(s,3H),3.21(s,3H),2.75-2.67(m,3H),2.5-2.45(m,1H),2.18-2.12(m,1H),2.04-2.00(m,1H)。 NMR analysis data of compound C3-4: 1 H NMR (400MHz, DMSO): δ8.52-8.51 (dd, 1H), 7.95-7.92 (dd, 1H), 7.39-7.36 (dd, 1H), 6.54-6.53 (m,1H),6.49(s,H),6.03(br,2H),3.73(s,3H),3.21(s,3H),2.75-2.67(m,3H),2.5-2.45(m,1H) ), 2.18-2.12 (m, 1H), 2.04-2.00 (m, 1H).
3、C3-5的合成3. Synthesis of C3-5
将6g化合物C3-4加入到500mL单口瓶中，加入氢氧化钯碳(2g)、乙酸乙酯(200mL)，于60℃氢气氛围下反应3天，过滤，滤液浓缩得粗品，柱层析得到2.5g化合物C3-5，直接用于下一步反应。Add 6g of compound C3-4 into a 500mL single-necked flask, add palladium hydroxide on carbon (2g) and ethyl acetate (200mL), react for 3 days under a hydrogen atmosphere at 60°C, filter, and concentrate the filtrate to obtain a crude product, which is obtained by column chromatography 2.5g of compound C3-5 was directly used in the next reaction.
4、C3-6的合成4. Synthesis of C3-6
将化合物C3-5(2.5g)加入到单口瓶中，再加入5％钯碳(2g)、甲苯(90mL)于空气中加热回流反应4天，过滤，滤液浓缩，柱层析得到2.3g化合物C3-6。Compound C3-5 (2.5g) was added to a single-necked flask, then 5% palladium on carbon (2g) and toluene (90mL) were heated and refluxed in the air for 4 days, filtered, the filtrate was concentrated, and 2.3g of compound was obtained by column chromatography. C3-6.
化合物C3-6的核磁分析数据： 1H NMR(400MHz,CDCl 3)：δ8.65-8.63(dd，1H),7.82-7.79(dd,1H),7.35-7.32(dd,1H),6.50-6.49(dd,1H),4.57-4.50(m,2H),4.20-4.10(m,1H),3.83-3.78(m,3H),3.34-3.30(m,3H),2.75-2.67(m,3H),2.56-2.52(m,1H),2.20-2.17(m,1H),2.13-1.97(m,3H),1.93-1.70(m,3H)。 Nuclear magnetic analysis data of compound C3-6: 1 H NMR (400MHz, CDCl 3 ): δ8.65-8.63(dd, 1H), 7.82-7.79(dd, 1H), 7.35-7.32(dd, 1H), 6.50- 6.49(dd,1H),4.57-4.50(m,2H),4.20-4.10(m,1H),3.83-3.78(m,3H),3.34-3.30(m,3H),2.75-2.67(m,3H) ), 2.56-2.52 (m, 1H), 2.20-2.17 (m, 1H), 2.13-1.97 (m, 3H), 1.93-1.70 (m, 3H).
5、C3-16的合成5. Synthesis of C3-16
将1.24g化合物C3-6溶于浓盐酸(30mL)中，保持温度于-5℃～5℃。将亚硝酸钠(1.36g)溶于水(8mL)中，滴加该溶液到上述反应中，保持该温度搅拌1h。将氯化亚铜(1.96g)的盐酸(8mL)混合物，滴加到反应中，保持温度搅拌1h，再于室温搅拌1h。将该反应液缓慢加入到氨水中，保持碱性，二氯甲烷萃取，浓缩得粗品。将该粗品加入到甲苯(80mL)和三氯氧磷(4.25mL)中，加热至100℃，搅拌3小时。浓缩，残留物加入碳酸氢钠水溶液，二氯甲烷萃取，干燥，浓缩，柱层析得0.55g化合物C3-16。1.24 g of compound C3-6 was dissolved in concentrated hydrochloric acid (30 mL), and the temperature was maintained at -5°C to 5°C. Sodium nitrite (1.36g) was dissolved in water (8mL), the solution was added dropwise to the above reaction, and the temperature was kept and stirred for 1 hour. A mixture of cuprous chloride (1.96 g) and hydrochloric acid (8 mL) was added dropwise to the reaction, and the mixture was stirred at the temperature for 1 h, and then stirred at room temperature for 1 h. The reaction solution was slowly added to ammonia water to keep alkaline, extracted with dichloromethane, and concentrated to obtain a crude product. The crude product was added to toluene (80 mL) and phosphorus oxychloride (4.25 mL), heated to 100°C, and stirred for 3 hours. Concentrate, add aqueous sodium bicarbonate to the residue, extract with dichloromethane, dry, concentrate, and column chromatography to obtain 0.55 g of compound C3-16.
化合物C3-16的核磁分析数据： 1H NMR(400MHz,CDCl3)：δ8.98-8.96(dd，1H),8.06-8.03(dd,1H),7.59-7.53(m,2H),4.24-4.14(m,1H),3.84-3.79(m,3H),3.33-3.30(m,3H),2.58-2.55(m,1H),2.24-1.85(m,6H),1.78-1.70(m,1H)。 NMR analysis data of compound C3-16: 1 H NMR (400MHz, CDCl3): δ 8.98-8.96 (dd, 1H), 8.06-8.03 (dd, 1H), 7.59-7.53 (m, 2H), 4.24-4.14 (m,1H),3.84-3.79(m,3H),3.33-3.30(m,3H),2.58-2.55(m,1H),2.24-1.85(m,6H),1.78-1.70(m,1H) .
6、C3-18的合成6. Synthesis of C3-18
于50mL单口瓶中加入化合物C3-16(487mg)、化合物C1-17(430mg)、三(二亚苄基丙酮)二钯(133mg)、2-二-叔丁膦基-2',4',6'-三异丙基联苯(123mg)、DBU(443mg)和乙二醇二甲醚(7.5mL)于60℃氩气保护下反应15小时。浓缩反应液，柱层析得到626mg化合物C3-18。Add compound C3-16 (487mg), compound C1-17 (430mg), tris(dibenzylideneacetone)dipalladium (133mg), 2-di-tert-butylphosphino-2',4',6 in a 50mL single-mouth flask '-Triisopropylbiphenyl (123mg), DBU (443mg) and ethylene glycol dimethyl ether (7.5mL) were reacted at 60°C under argon protection for 15 hours. The reaction solution was concentrated, and column chromatography was performed to obtain 626 mg of compound C3-18.
化合物C3-18的核磁分析数据：1H NMR(400MHz,CDCl3)：δ8.73-8.72(dd,1H),8.00-7.96(m,1H),7.71-7.65(d,1H),7.43-7.40(m,1H),7.12-7.08(d,1H),6.19-6.18(d,1H),4.25-4.17(m,1H),3.84-3.79(d,3H),3.35-3.30(d,3H),2.57-2.53(m,4H),2.22- 2.18(m,1H),2.11-1.99(m,3H),1.93-1.83(m,2H),1.79-1.72(m,1H),1.68(s,9H)。NMR analysis data of compound C3-18: 1H NMR (400MHz, CDCl3): δ8.73-8.72(dd,1H),8.00-7.96(m,1H),7.71-7.65(d,1H),7.43-7.40( m,1H),7.12-7.08(d,1H),6.19-6.18(d,1H),4.25-4.17(m,1H),3.84-3.79(d,3H),3.35-3.30(d,3H), 2.57-2.53(m,4H),2.22- 2.18(m,1H),2.11-1.99(m,3H),1.93-1.83(m,2H),1.79-1.72(m,1H),1.68(s,9H) ).
7、C3-19的合成7. Synthesis of C3-19
于50mL单口瓶中加入化合物C3-18(576mg)、LiOH·H2O(153mg)、的四氢呋喃/甲醇/水(17：1：1，21mL)，60℃搅拌15小时，LC-MS显示原料未反应完全，补加LiOH·H 2O(50mg)，继续搅拌15小时。加入甲基叔丁基醚和水，水相蒸干得粗品C3-19，直接用于下一步反应。 Add compound C3-18 (576mg), LiOH·H2O (153mg), tetrahydrofuran/methanol/water (17:1:1, 21mL) into a 50mL single-neck flask, stir at 60°C for 15 hours, LC-MS shows that the raw material is unreacted Complete, add LiOH·H 2 O (50 mg) and continue stirring for 15 hours. Methyl tert-butyl ether and water were added, and the water phase was evaporated to dryness to obtain crude product C3-19, which was directly used in the next reaction.
8、C3和C4的合成8. Synthesis of C3 and C4
于50mL单口瓶中加入化合物C3-19(387mg)、化合物C1-7(279mg)、二异丙基乙胺(1g)和DMF(6mL)，搅拌下加入HATU(570mg)，室温搅拌1小时，加入水，二氯甲烷萃取3次，有机相用水洗涤，干燥，浓缩，柱层析得到粗品，制备分离得到化合物C3和C4。Add compound C3-19 (387mg), compound C1-7 (279mg), diisopropylethylamine (1g) and DMF (6mL) into a 50mL single-neck flask, add HATU (570mg) with stirring, and stir at room temperature for 1 hour. Add water, extract with dichloromethane three times, wash the organic phase with water, dry, concentrate, and obtain a crude product by column chromatography, and prepare and separate compounds C3 and C4.
C3和C4的分离由waters高效液相色谱仪分离，制备分离的条件如下：The separation of C3 and C4 is separated by waters high performance liquid chromatograph. The conditions of preparation and separation are as follows:
仪器：watersInstrument: waters
色谱柱：innovalODS-2/C18(30×100mm,5μm)Column: innovativeODS-2/C18 (30×100mm,5μm)
流动相：A相：水(含0.1％三氟乙酸)Mobile phase: Phase A: water (containing 0.1% trifluoroacetic acid)
B相：甲醇Phase B: Methanol
流速：15.0ml/min，检测波长：254nmFlow rate: 15.0ml/min, detection wavelength: 254nm
溶剂：甲醇-水(1︰1)Solvent: methanol-water (1:1)
进样浓度：约15mg/mlInjection concentration: about 15mg/ml
进样量：2mlInjection volume: 2ml
出峰时间：15.8min/17.8minPeak time: 15.8min/17.8min
梯度程序：Gradient program:
Figure PCTCN2020091425-appb-000136
Figure PCTCN2020091425-appb-000136
化合物C4的核磁分析数据：1H NMR(400MHz,CDCl3)：δ8.70-8.68(dd,1H),8.39-8.38(m,2H),7.93-7.90(d,2H),7.90-7.76(dd,1H),7.59-7.58(d,1H),7.40-7.37(dd,1H),7.32(s,1H),6.86-6.84(d,1H),6.01(s,1H),5.24-5.16(m,1H),4.25-4.20(m,1H),3.31(s,3H),2.34(s,3H),2.22-1.96(m,6H),1.91-1.86(m,2H),1.59-1.57(d,3H)。NMR analysis data of compound C4: 1H NMR (400MHz, CDCl3): δ8.70-8.68 (dd, 1H), 8.39-8.38 (m, 2H), 7.93-7.90 (d, 2H), 7.90-7.76 (dd, 1H), 7.59-7.58 (d, 1H), 7.40-7.37 (dd, 1H), 7.32 (s, 1H), 6.86-6.84 (d, 1H), 6.01 (s, 1H), 5.24-5.16 (m, 1H), 4.25-4.20 (m, 1H), 3.31 (s, 3H), 2.34 (s, 3H), 2.22-1.96 (m, 6H), 1.91-1.86 (m, 2H), 1.59-1.57 (d, 3H).
实施例3Example 3
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000137
Figure PCTCN2020091425-appb-000137
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000138
Figure PCTCN2020091425-appb-000138
1、C5-1的合成1. Synthesis of C5-1
于250mL单口瓶中加入化合物C3-18(0.91g)、氢氧化钯碳(600mg)、乙酸乙酯(20mL)和甲醇(20mL)，在H 2氛围下室温搅拌48h，TLC显示反应完全。过滤，浓缩得到粗品，直接用于下一步。 Compound C3-18 (0.91 g), palladium hydroxide on carbon (600 mg), ethyl acetate (20 mL) and methanol (20 mL) were added to a 250 mL single-neck flask, and stirred at room temperature under H 2 atmosphere for 48 h. TLC showed that the reaction was complete. Filter and concentrate to obtain the crude product, which is directly used in the next step.
2、C5-2的合成2. Synthesis of C5-2
于50mL单口瓶中加入化合物C5-1(0.87g)、甲醛水溶液(37％，565mg)、醋酸(418mg)、四氢呋喃(16mL)。搅拌10分钟后，加入三乙酰氧基硼氢化钠(1.84g)，室温搅拌过夜。TLC显示反应完全，加入水，用乙酸乙酯萃取，干燥浓缩，柱层析得到0.84g C5-2。Compound C5-1 (0.87 g), aqueous formaldehyde solution (37%, 565 mg), acetic acid (418 mg), and tetrahydrofuran (16 mL) were added to a 50 mL single-mouth flask. After stirring for 10 minutes, sodium triacetoxyborohydride (1.84 g) was added, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was complete, add water, extract with ethyl acetate, dry and concentrate, and column chromatography to obtain 0.84g C5-2.
化合物C5-2的核磁分析数据：1H NMR(400MHz,CDCl3)：δ6.90-6.89(d,1H),6.67-6.64(d,1H),6.57-6.49(d,1H),3.83-3.78(d,3H),3.56-3.28(d,3H),3.17-3.05(m,4H),2.76-2.72(m,2H),2.65-2.64(d,3H),2.59-2.52(d,3H),2.50-2.48(m,1H),2.16-2.07(m,2H),1.91-1.75(m,6H),1.61-1.59(m,2H)。NMR analysis data of compound C5-2: 1H NMR (400MHz, CDCl3): δ6.90-6.89(d,1H),6.67-6.64(d,1H),6.57-6.49(d,1H),3.83-3.78( d,3H),3.56-3.28(d,3H),3.17-3.05(m,4H),2.76-2.72(m,2H),2.65-2.64(d,3H), 2.59-2.52(d,3H), 2.50-2.48 (m, 1H), 2.16-2.07 (m, 2H), 1.91-1.75 (m, 6H), 1.61-1.59 (m, 2H).
3、C5-3的合成3. Synthesis of C5-3
50mL单口瓶中加入化合物C5-2(0.8g)、氢氧化锂一水合物(261mg)和THF/MeOH/H 2O(15：1：1，26mL)，在60℃反应14h。浓缩，甲苯带水除去水分得到C5-3粗品，直接用于下一步。 Compound C5-2 (0.8 g), lithium hydroxide monohydrate (261 mg) and THF/MeOH/H 2 O (15:1:1, 26 mL) were added to a 50 mL single-neck flask, and reacted at 60°C for 14 hours. Concentrate, toluene with water to remove water to obtain crude C5-3, which is directly used in the next step.
4、C5和C6的合成4. Synthesis of C5 and C6
于50mL单口瓶中加入粗品化合物C5-3(399mg)、化合物C1-7(279mg)、二异丙基乙胺(1g)和DMF(6mL)，搅拌下加入HATU(570mg)，室温搅拌过夜，加入水，乙酸乙酯萃取3次，有机相用水洗涤，干燥，浓缩，柱层析得到粗品，制备分离得到化合物C5和C6。Add crude compound C5-3 (399mg), compound C1-7 (279mg), diisopropylethylamine (1g) and DMF (6mL) into a 50mL single-necked flask, add HATU (570mg) with stirring, and stir at room temperature overnight. Water was added, ethyl acetate was extracted 3 times, the organic phase was washed with water, dried, concentrated, and column chromatography was used to obtain a crude product, which was prepared and separated to obtain compounds C5 and C6.
化合物C6的核磁分析数据：1H NMR(400MHz,CDCl3)：δ8.38-8.37(m,2H),7.91-7.90(d,1H),7.78-7.75(dd,1H),7.58-7.57(d,1H),6.89-6.87(d,1H),6.32(br,1H),5.20-5.13(m,1H),3.34(s,3H),3.20-3.18(m,1H),3.05-3.03(m,2H),2.75-2.71(m,2H),2.64(s,3H),2.30(s,3H),2.05-1.81(m,8H),1.62-1.56(m,8H)。NMR analysis data of compound C6: 1H NMR (400MHz, CDCl3): δ8.38-8.37(m,2H),7.91-7.90(d,1H),7.78-7.75(dd,1H),7.58-7.57(d, 1H), 6.89-6.87 (d, 1H), 6.32 (br, 1H), 5.20-5.13 (m, 1H), 3.34 (s, 3H), 3.20-3.18 (m, 1H), 3.05-3.03 (m, 2H), 2.75-2.71 (m, 2H), 2.64 (s, 3H), 2.30 (s, 3H), 2.05-1.81 (m, 8H), 1.62-1.56 (m, 8H).
实施例4Example 4
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000139
Figure PCTCN2020091425-appb-000139
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000140
Figure PCTCN2020091425-appb-000140
1、C7-1的合成1. Synthesis of C7-1
于50mL单口瓶中加入C1-4(186mg，0.51mmol)、LiOH·H 2O(43mg，1mmol)、MeOH/H 2O(5mL/1mL)，将反应置于50℃下反应过夜。LC-MS显示反应完毕，浓缩得粗品100mg。 C1-4 (186 mg, 0.51 mmol), LiOH·H 2 O (43 mg, 1 mmol), MeOH/H 2 O (5 mL/1 mL) were added to a 50 mL single-neck flask, and the reaction was placed at 50° C. to react overnight. LC-MS showed that the reaction was complete, and it was concentrated to obtain 100 mg of crude product.
2、C7的合成2. Synthesis of C7
于50mL单口瓶中加入C7-1(83mg，0.24mmol)、DMF(2mL)、HATU(134mg，0.35mmol)，室温搅拌下加入二异丙基乙胺(243mg，1.88mmol)、C1-7(72mg，0.26mmol)，将反应置于50℃下反应。LC-MS显示反应完毕，将反应液倒入20mL水中乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，旋干，制备分离得C7(17mg，purity:89.9％)，[M+H]:542.3。C7-1 (83mg, 0.24mmol), DMF (2mL), HATU (134mg, 0.35mmol) were added to a 50mL single-mouth flask, and diisopropylethylamine (243mg, 1.88mmol), C1-7 ( 72mg, 0.26mmol), the reaction was placed at 50°C for reaction. LC-MS showed that the reaction was complete. The reaction solution was poured into 20 mL of water and extracted 3 times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to prepare and separate C7 (17mg, purity: 89.9%), [M+ H]: 542.3.
化合物C7的核磁分析数据：1H NMR(400MHz,DMSO)δ11.99(s,1H),9.91(s,1H),8.66(dd,J＝22.0,5.9Hz,2H),8.45(s,1H),8.01(t,J＝5.9Hz,1H),7.88(ddd,J＝18.7,12.7,6.6Hz,3H),7.18(s,1H),6.30(s,1H),6.14(s,1H),5.10(s,1H),3.16(s,3H),2.76–2.55(m,2H),2.33(s,1H),2.19(d,J＝11.9Hz,3H),2.14–1.65(m,3H),1.49(d,J＝6.7Hz,3H).NMR analysis data of compound C7: 1H NMR(400MHz,DMSO)δ11.99(s,1H),9.91(s,1H),8.66(dd,J=22.0,5.9Hz,2H),8.45(s,1H) ,8.01(t,J=5.9Hz,1H),7.88(ddd,J=18.7,12.7,6.6Hz,3H),7.18(s,1H),6.30(s,1H),6.14(s,1H), 5.10 (s, 1H), 3.16 (s, 3H), 2.76-2.55 (m, 2H), 2.33 (s, 1H), 2.19 (d, J = 11.9 Hz, 3H), 2.14-1.65 (m, 3H) ,1.49(d,J=6.7Hz,3H).
实施例5Example 5
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000141
Figure PCTCN2020091425-appb-000141
合成路线及实验过程如下The synthetic route and experimental process are as follows
Figure PCTCN2020091425-appb-000142
Figure PCTCN2020091425-appb-000142
1、C8-1的合成1. Synthesis of C8-1
于250mL单口瓶中加入C3-4(4.0g,12.8mmol)、浓盐酸(60mL)，冰盐浴降温至-10℃，缓慢加入NaNO 2(4.4g,63.9mmol)的水溶液，控制温度在0℃以下，搅拌30min，滴加CuCl(6.3g,63.9mmol)的浓盐酸悬浊液，移至室温反应1h。LC-MS显示反应完毕，将反应液缓慢倒入氨水中，DCM萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干，柱层析得2.3g产物。 Add C3-4 (4.0g, 12.8mmol) and concentrated hydrochloric acid (60mL) into a 250mL single-necked flask. Cool down to -10℃ in an ice salt bath. Slowly add an aqueous solution of NaNO 2 (4.4g, 63.9mmol) and control the temperature at 0 Below ℃, stir for 30min, add CuCl (6.3g, 63.9mmol) concentrated hydrochloric acid suspension dropwise, move to room temperature and react for 1h. LC-MS showed that the reaction was complete, the reaction solution was slowly poured into ammonia water, extracted with DCM three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatography yielded 2.3 g of product.
2、C8-2的合成2. Synthesis of C8-2
于50mL单口瓶中加入C8-1(487mg,1.5mmol)、C1-17(433mg,2.2)、Pd 2(dba) 3(137mg,0.15mmol)、t-BuXPhos(127mg,0.3mmol)、DBU(456mg,3mmol)、(CH 3OCH 2) 2(8mL)，N 2氛围下将反应置于60℃下反应过夜。LC-MS显示反应完毕，浓缩，柱层析得产品525mg。 Add C8-1 (487mg, 1.5mmol), C1-17 (433mg, 2.2), Pd 2 (dba) 3 (137mg, 0.15mmol), t-BuXPhos (127mg, 0.3mmol), DBU ( 456 mg, 3 mmol), (CH 3 OCH 2 ) 2 (8 mL), and the reaction was placed at 60° C. overnight under N 2 atmosphere. LC-MS showed that the reaction was complete, and the product was concentrated and 525 mg was obtained by column chromatography.
3、C8-3的合成3. Synthesis of C8-3
于50mL单口瓶中加入C8-2(475mg，0.963mmol)、LiOH·H 2O(121mg，2.89mmol)、THF/MeOH/H 2O(7mL/7mL/4mL)，将反应置于60℃下反应过夜。LC-MS显示反应完毕，浓缩得粗品481mg。 Add C8-2 (475mg, 0.963mmol), LiOH·H 2 O (121mg, 2.89mmol), THF/MeOH/H 2 O (7mL/7mL/4mL) into a 50mL single-mouth flask, and place the reaction at 60°C React overnight. LC-MS showed that the reaction was complete, and it was concentrated to obtain 481 mg of crude product.
4、C8的合成4. Synthesis of C8
于50mL单口瓶中加入C8-3(390mg，1mmol)、C1-7(280mg,1mmol)、DMF(6mL)、二异丙基乙胺(1.03g，8mmol)，室温搅拌下加入HATU(570mg，1.5mmol)，将反应置于25℃下反应1h。LC-MS显示反应完毕，将反应液倒入水(60mL)中，乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，旋干，柱层析得粗品后再制备分离得C8(291mg，purity：95.3％)，[M+H]:568.3。C8-3 (390mg, 1mmol), C1-7 (280mg, 1mmol), DMF (6mL), diisopropylethylamine (1.03g, 8mmol) were added to a 50mL single-necked flask, and HATU (570mg, 1.5mmol), the reaction was placed at 25°C for 1h. LC-MS showed that the reaction was complete, the reaction solution was poured into water (60mL), extracted with ethyl acetate 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, column chromatography to obtain the crude product and then prepared and separated to obtain C8( 291 mg, purity: 95.3%), [M+H]: 568.3.
化合物C8的核磁分析数据：1H NMR(400MHz,DMSO)δ11.77(s,1H),9.16(d,J＝3.9Hz,1H),8.70(ddd,J＝4.5,1.7,0.8Hz,1H),8.66–8.55(m,2H),8.47(t,J＝2.5Hz,1H),8.09(d,J＝8.5Hz,1H),8.03(ddd,J＝8.0,5.5,2.3Hz,1H),7.91(ddd,J＝13.5,6.4,2.8Hz,2H),7.74(s,1H),7.47(ddd,J＝8.4,4.0,2.3Hz,1H),6.66(s,1H),5.86(d,J＝5.6Hz,1H),5.19–5.04(m,1H),3.19(d,J＝3.3Hz,3H),2.84–2.52(m,4H),2.21(d,J＝3.8Hz,3H),2.19–1.90(m,2H),1.51(dd,J＝7.0,2.2Hz,3H).NMR analysis data of compound C8: 1H NMR(400MHz,DMSO)δ11.77(s,1H),9.16(d,J=3.9Hz,1H),8.70(ddd,J=4.5,1.7,0.8Hz,1H) ,8.66-8.55(m,2H),8.47(t,J=2.5Hz,1H), 8.09(d,J=8.5Hz,1H), 8.03(ddd,J=8.0,5.5,2.3Hz,1H), 7.91(ddd,J=13.5,6.4,2.8Hz,2H),7.74(s,1H),7.47(ddd,J=8.4,4.0,2.3Hz,1H),6.66(s,1H),5.86(d, J=5.6Hz,1H), 5.19–5.04(m,1H), 3.19(d,J=3.3Hz,3H), 2.84–2.52(m,4H), 2.21(d,J=3.8Hz,3H), 2.19–1.90(m,2H), 1.51(dd,J=7.0,2.2Hz,3H).
实施例6Example 6
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000143
Figure PCTCN2020091425-appb-000143
合成路线及实验过程如下The synthetic route and experimental process are as follows
Figure PCTCN2020091425-appb-000144
Figure PCTCN2020091425-appb-000144
1、C9-2的合成1. Synthesis of C9-2
于250mL单口瓶中加入3-氨基-5-甲基吡唑(427mg，4.4mmol)、C9-1(764mg，4mmol)、DMSO(8mL)、二异丙基乙胺(581mg，4.5mmol)，将反应置于90℃下反应4h。LC-MS显示反应完毕，搅拌下将反应液倒入水(100mL)中有固体析出，过滤，水洗滤饼，将滤饼干燥得产品1.14g。Add 3-amino-5-methylpyrazole (427mg, 4.4mmol), C9-1 (764mg, 4mmol), DMSO (8mL), diisopropylethylamine (581mg, 4.5mmol) into a 250mL single-necked flask, The reaction was placed at 90°C for 4h. LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (100 mL) to precipitate solids, filtered, and the filter cake was washed with water, and the filter cake was dried to obtain 1.14 g of the product.
2、C9-3的合成2. Synthesis of C9-3
于50mL单口瓶中加入C9-2(796mg，3.16mmol)、C1-3(935mg，3.16mmol)、Pd(PPh 3) 4(365mg，0.32mmol)、K 2CO 3(654mg，4.74mmol)、二氧六环/H 2O(9mL/1.5mL)，N 2保护下将反应置于100℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入水(100mL)中，乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得到产品775mg。 Add C9-2 (796mg, 3.16mmol), C1-3 (935mg, 3.16mmol), Pd(PPh 3 ) 4 (365mg, 0.32mmol), K 2 CO 3 (654mg, 4.74mmol), The reaction was placed at 100°C overnight under the protection of dioxane/H 2 O (9 mL/1.5 mL) and N 2 . LC-MS showed that the reaction was complete, the reaction solution was poured into water (100 mL) under stirring, and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain 775 mg of product.
3、C9-4的合成3. Synthesis of C9-4
于50mL单口瓶中加入C12-3(700mg,1.8mmol)、Pd(OH) 2/C(10％，350mg)、MeOH(15mL)，H 2(60psi)氛围下将反应置于50℃下反应过夜。LC-MS显示大部分原料反应完毕，过滤，浓缩，柱层析，得C9-3与C9-4的混合物(242mg)直接用于下一步反应。 Add C12-3 (700mg, 1.8mmol), Pd(OH) 2 /C (10%, 350mg), MeOH (15mL), H 2 (60psi) into a 50mL single-necked flask, and place the reaction at 50℃ for reaction overnight. LC-MS showed that the reaction of most of the raw materials was completed, filtered, concentrated, and column chromatographed to obtain a mixture of C9-3 and C9-4 (242 mg) and used directly in the next reaction.
4、C9-5和C9-6的合成4. Synthesis of C9-5 and C9-6
于50mL单口瓶中加入C9-3与C9-4的混合物(230mg，0.59mmol)、LiOH·H 2O(100mg，2.4mmol)、MeOH/H 2O(3mL/1.5mL)，将反应置于50℃下反应过夜。LC-MS显示反应完毕，浓缩得粗品250mg直接用于下一步反应。 Add a mixture of C9-3 and C9-4 (230mg, 0.59mmol), LiOH·H 2 O (100mg, 2.4mmol), MeOH/H 2 O (3mL/1.5mL) into a 50mL single-neck flask, and place the reaction in React overnight at 50°C. LC-MS showed that the reaction was complete, and 250 mg of crude product was obtained by concentration and used directly in the next reaction.
5、化合物C9、C10、C11的合成5. Synthesis of compounds C9, C10, C11
于50mL单口瓶中加入C9-5和C9-6混合物(114mg，0.3mmol)、C1-7(66mg，0.24mmol)、DMF(3mL)，室温搅拌下加入二异丙基乙胺(397mg，3mmol)、PyBop(234mg，0.45mmol)、HOBT(84mg,0.4mmol)将反应置于室温下反应30分钟。LC-MS显示反应完毕，将反应液倒入水(30mL)中乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品后制备分离得化合物C11(10mg，purity:96.7％)，[M+H]:560.2；化合物C10(19mg，purity:97.5％)，[M+H]:562.3；化合物C9(17mg，purity:97.1％)，[M+H]:562.3。Add the mixture of C9-5 and C9-6 (114mg, 0.3mmol), C1-7 (66mg, 0.24mmol), DMF (3mL) to a 50mL single-mouth flask, add diisopropylethylamine (397mg, 3mmol) under stirring at room temperature ), PyBop (234mg, 0.45mmol), HOBT (84mg, 0.4mmol) The reaction was placed at room temperature for 30 minutes. LC-MS showed that the reaction was complete. The reaction solution was poured into water (30mL) and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was prepared and isolated to obtain compound C11 (10mg, purity: 96.7%), [M+H]: 560.2; compound C10 (19 mg, purity: 97.5%), [M+H]: 562.3; compound C9 (17 mg, purity: 97.1%), [M+H]: 562.3.
实施例7Example 7
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000145
Figure PCTCN2020091425-appb-000145
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000146
Figure PCTCN2020091425-appb-000146
1、C12-2的合成1. Synthesis of C12-2
于250mL单口瓶中加入3-氨基-5-甲基吡唑(426mg，4.4mmol)、C12-1(696 mg，4mmol)、DMSO(4mL)、二异丙基乙胺(1.032g，8mmol)，将反应置于90℃下反应5h。LC-MS显示反应完毕，搅拌下将反应液倒入水(40mL)中有固体析出，过滤，水洗滤饼，将滤饼干燥，得产物910mg。Add 3-amino-5-methylpyrazole (426mg, 4.4mmol), C12-1 (696 mg, 4mmol), DMSO (4mL), and diisopropylethylamine (1.032g, 8mmol) into a 250mL single-mouth bottle , The reaction was placed at 90 ℃ for 5h. LC-MS showed that the reaction was complete, the reaction solution was poured into water (40 mL) under stirring, and solids precipitated, filtered, washed the filter cake with water, and dried the filter cake to obtain 910 mg of product.
2、C12-3的合成2. Synthesis of C12-3
于50mL单口瓶中加入C12-2(585mg，2.5mmol)、C1-3(814mg，2.75mmol)、Pd(PPh 3) 4(289mg，0.25mmol)、K 2CO 3(690mg，5mmol)、二氧六环/H 2O(30mL/4mL)，N 2保护下将反应置于100℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入水(100mL)中乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析，得产品747mg。 Add C12-2 (585mg, 2.5mmol), C1-3 (814mg, 2.75mmol), Pd(PPh 3 ) 4 (289mg, 0.25mmol), K 2 CO 3 (690mg, 5mmol), two in a 50mL single-mouth bottle The reaction was placed at 100°C overnight under the protection of oxane/H 2 O (30 mL/4 mL) and N 2 . LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain 747 mg of product.
3、C12-4的合成3. Synthesis of C12-4
于150mL单口瓶中加入C12-3(747mg,2mmol)、Pd(OH) 2/C(10％，700mg)、EtOH(100mL)，H 2氛围下将反应置于80℃下反应过夜。LC-MS显示大部分原料反应完毕，过滤，浓缩，柱层析得C12-4与C12-3的混合物291mg，直接用于下一步反应。 C12-3 (747 mg, 2 mmol), Pd(OH) 2 /C (10%, 700 mg), EtOH (100 mL) were added to a 150 mL single-mouth flask, and the reaction was placed at 80° C. overnight under H 2 atmosphere. LC-MS showed that the reaction of most of the raw materials was completed, filtered, concentrated, and column chromatography obtained 291 mg of a mixture of C12-4 and C12-3, which was directly used in the next reaction.
4、C12-5和C12-6的合成4. Synthesis of C12-5 and C12-6
于50mL单口瓶中加入C12-4与C12-3的混合物(291mg，0.79mmol)、LiOH·H 2O(132mg，3.15mmol)、MeOH/H 2O(15mL/3mL)，将反应置于50℃下反应过夜。LC-MS显示反应完毕，浓缩得粗品393mg，直接用于下一步反应。 A mixture of C12-4 and C12-3 (291 mg, 0.79 mmol), LiOH·H 2 O (132 mg, 3.15 mmol), MeOH/H 2 O (15 mL/3 mL) was added to a 50 mL single-mouth flask, and the reaction was placed at 50 React overnight at °C. LC-MS showed that the reaction was complete, and it was concentrated to obtain 393 mg of crude product, which was directly used in the next reaction.
5、C12和C13的合成5. Synthesis of C12 and C13
于50mL单口瓶中加入C12-5和C12-6的混合物(197mg，0.55mmol)、C1-7(122mg，0.44mmol)、DMF(10mL)，室温搅拌下加入二异丙基乙胺(705mg，5.5mmol)、PyBop(426mg，0.81mmol)、HOBT(150mg,1.08mmol)将反应置于室温下反应30分钟。LC-MS显示反应完毕，将反应液倒入水(100mL)中，乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩柱层析得粗品，然后制备分离得C13(26mg，purity:96.5％)，C12(13mg，purity:97.5％)。A mixture of C12-5 and C12-6 (197mg, 0.55mmol), C1-7 (122mg, 0.44mmol), DMF (10mL) was added to a 50mL single-mouth flask, and diisopropylethylamine (705mg, 5.5mmol), PyBop (426mg, 0.81mmol), HOBT (150mg, 1.08mmol) The reaction was placed at room temperature for 30 minutes. LC-MS showed that the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by column chromatography to obtain the crude product, and then prepared and separated C13 (26 mg, purity: 96.5%), C12 (13 mg, purity: 97.5%).
实施例8Example 8
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000147
Figure PCTCN2020091425-appb-000147
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000148
Figure PCTCN2020091425-appb-000148
1、C14-2的合成1. Synthesis of C14-2
于250mL单口瓶中加入3-氨基-5-甲基吡唑(540mg，5.5mmol)、C14-1(1.04g，5mmol)、DMSO(10mL)、二异丙基乙胺(1.29g，10mmol)，将反应置于90℃下反应5h。LC-MS显示反应完毕，搅拌下将反应液倒入水(40mL)中有固体析出，过滤，水洗滤饼，将滤饼干燥得产品1.2g。Add 3-amino-5-methylpyrazole (540mg, 5.5mmol), C14-1 (1.04g, 5mmol), DMSO (10mL), and diisopropylethylamine (1.29g, 10mmol) into a 250mL single-mouth flask. , The reaction was placed at 90 ℃ for 5h. LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (40 mL), and solids precipitated, filtered, washed the filter cake with water, and dried the filter cake to obtain 1.2 g of product.
2、C14-3的合成2. Synthesis of C14-3
于100mL单口瓶中加入C14-2(774mg，2.88mmol)、C1-3(1.7g，5.75mmol)、Pd(PPh 3) 4(999mg，0.864mmol)、K 2CO 3(1.19g，8.64mmol)、二氧六环/H 2O(40mL/10mL)，N 2保护下将反应置于90℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入水(100mL)中乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得1.16g产品。 Add C14-2 (774mg, 2.88mmol), C1-3 (1.7g, 5.75mmol), Pd(PPh 3 ) 4 (999mg, 0.864mmol), K 2 CO 3 (1.19g, 8.64mmol) into a 100mL single-mouth bottle ), dioxane/H 2 O (40 mL/10 mL), and place the reaction at 90° C. overnight under the protection of N 2 . LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography yielded 1.16 g of product.
3、C14-4的合成3. Synthesis of C14-4
于50mL单口瓶中加入C14-3(302mg,0.74mmol)、Pd(OH) 2/C(10％，30mg)、MeOH(20mL)，H 2氛围下将反应置于50℃下反应。LC-MS显示反应完毕，过滤，浓缩，柱层析得产物90mg。 C14-3 (302 mg, 0.74 mmol), Pd(OH) 2 /C (10%, 30 mg), MeOH (20 mL) were added to a 50 mL single-mouth flask, and the reaction was placed at 50° C. under an H 2 atmosphere. LC-MS showed that the reaction was complete, filtered, concentrated, and column chromatography to obtain 90 mg of the product.
4、C14-5的合成4. Synthesis of C14-5
于50mL单口瓶中加入C14-4(374mg，1mmol)、乙二醛(174mg，1.2mmol)、乙醇(10mL)，室温下反应过夜。LC-MS显示反应完毕，浓缩，柱层析得产品94mg。C14-4 (374 mg, 1 mmol), glyoxal (174 mg, 1.2 mmol), ethanol (10 mL) were added to a 50 mL single-necked flask, and reacted overnight at room temperature. LC-MS showed that the reaction was complete, concentrated, and column chromatography gave 94 mg of product.
5、C14-6的合成5. Synthesis of C14-6
于50mL单口瓶中加入C14-5(94mg，0.24mmol)、LiOH·H 2O(20mg，0.48mmol)、MeOH/H 2O(2mL/0.5mL)，将反应置于50℃下反应48h。LC-MS显示反应完毕，浓缩得粗品106mg，直接用于下一步反应。 C14-5 (94 mg, 0.24 mmol), LiOH·H 2 O (20 mg, 0.48 mmol), MeOH/H 2 O (2 mL/0.5 mL) were added to a 50 mL single-mouth flask, and the reaction was placed at 50° C. for 48 hours. LC-MS showed that the reaction was complete, and the crude product was concentrated to obtain 106 mg, which was directly used in the next reaction.
6、C14的合成6. Synthesis of C14
于50mL单口瓶中加入C14-6粗品(106mg，0.17mmol)、C1-7(52mg，1.97mmol)、DMF(1mL)、二异丙基乙胺(176mg，1.36mmol)，室温搅拌10min，加入PyBop(133mg，0.26mmol)将反应置于室温下反应30min。LC-MS显示反应完毕，将反应液倒入水(100mL)中，乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得粗品，粗品制备分离得C14(37mg，purity:98％)。Add crude C14-6 (106mg, 0.17mmol), C1-7 (52mg, 1.97mmol), DMF (1mL), and diisopropylethylamine (176mg, 1.36mmol) into a 50mL single-neck flask, stir at room temperature for 10min, add PyBop (133 mg, 0.26 mmol) was left at room temperature for 30 min. LC-MS showed that the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain a crude product. The crude product was prepared and separated Obtained C14 (37mg, purity: 98%).
实施例9Example 9
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000149
Figure PCTCN2020091425-appb-000149
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000150
Figure PCTCN2020091425-appb-000150
1、C15-2的合成1. Synthesis of C15-2
于100mL单口瓶中加入C15-1(1g)、三乙胺(1.45mL)、乙醇(20mL)和四氢呋喃(5mL)，搅拌下分批加入3-氨基-5-甲基吡唑(530mg)，室温搅拌过夜。TLC显示反应完全，浓缩，残渣加入水，搅拌15分钟，过滤，滤饼用***洗涤，干燥得化合物C18-2。Add C15-1 (1g), triethylamine (1.45mL), ethanol (20mL) and tetrahydrofuran (5mL) into a 100mL single-neck flask, and add 3-amino-5-methylpyrazole (530mg) in batches with stirring. Stir at room temperature overnight. TLC showed that the reaction was complete, concentrated, the residue was added with water, stirred for 15 minutes, filtered, the filter cake was washed with ether and dried to obtain compound C18-2.
2、C15-3的合成2. Synthesis of C15-3
于100mL单口瓶中加入C15-2(973mg，3.75mmol)、C1-3(1.66g，5.62mmol)、Pd(PPh 3) 4(2.17g，1.875mmol)、Cs 2CO 3(3.67g，11.25mmol)、二氧六环/H 2O(15mL/3mL)，N 2保护下将反应置于110℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入水(100mL)中，乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩柱层析得到产品895mg。 Add C15-2 (973mg, 3.75mmol), C1-3 (1.66g, 5.62mmol), Pd(PPh 3 ) 4 (2.17g, 1.875mmol), Cs 2 CO 3 (3.67g, 11.25mmol) into a 100mL single-mouth bottle mmol), dioxane/H 2 O (15 mL/3 mL), and the reaction was placed at 110° C. overnight under the protection of N 2 . LC-MS showed that the reaction was complete, the reaction solution was poured into water (100 mL) under stirring, and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 895 mg of product.
3、C15-4的合成3. Synthesis of C15-4
于50mL单口瓶中加入C15-3(875mg,2.23mmol)、Pd(OH) 2/C(10％，170mg)、MeOH(50mL)，H 2氛围下将反应置于50℃下反应。LC-MS监测反应完毕，过滤，浓缩得粗产物724mg。 C15-3 (875 mg, 2.23 mmol), Pd(OH) 2 /C (10%, 170 mg), MeOH (50 mL) were added to a 50 mL single-mouth flask, and the reaction was placed at 50° C. under an H 2 atmosphere. LC-MS monitored the completion of the reaction, filtered and concentrated to obtain 724 mg of crude product.
4、C15-5的合成4. Synthesis of C15-5
于50mL单口瓶中加入C15-4(675mg，1.7mmol)、LiOH·H 2O(145mg，3.4mmol)、MeOH/H 2O(5mL/1mL)，将反应置于50℃下反应过夜。LC-MS显示反应完毕，浓缩得粗品210mg，直接用于下一步反应。 C15-4 (675 mg, 1.7 mmol), LiOH·H 2 O (145 mg, 3.4 mmol), MeOH/H 2 O (5 mL/1 mL) were added to a 50 mL single-mouth flask, and the reaction was placed at 50° C. overnight. LC-MS showed that the reaction was complete, and it was concentrated to obtain 210 mg of crude product, which was directly used in the next reaction.
5、C15的合成5. Synthesis of C15
于50mL单口瓶中加入C15-5(148mg，0.39mmol)、C1-7(119mg，0.43 mmol)、DMF(2mL)、二异丙基乙胺(401mg，3.1mmol)，室温搅拌10min，加入PyBop(304mg，0.58mmol)将反应置于室温下反应30min。LC-MS显示反应完毕，将反应液倒入水(30mL)中，乙酸乙酯萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩柱层析得粗品，然后制备分离得C15(10mg，purity:91％)。Add C15-5 (148mg, 0.39mmol), C1-7 (119mg, 0.43mmol), DMF (2mL), diisopropylethylamine (401mg, 3.1mmol) into a 50mL single-necked flask, stir at room temperature for 10min, add PyBop (304mg, 0.58mmol) The reaction was placed at room temperature for 30 min. LC-MS showed that the reaction was complete, the reaction solution was poured into water (30 mL), extracted with ethyl acetate 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by column chromatography to obtain the crude product, and then prepared and separated C15 (10mg, purity: 91%).
实施例10Example 10
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000151
Figure PCTCN2020091425-appb-000151
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000152
Figure PCTCN2020091425-appb-000152
1、C16-2的合成1. Synthesis of C16-2
50mL反应瓶依次加入C16-1(20mmol,3.8g)、3-氨基-5-甲基吡唑(24mmol,2.4g)、二异丙基乙胺(40mmol,5.2g)和DMSO(30mL)，氩气保护下将反应置于90℃下反应16h。TLC显示反应完全，加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过四氢呋喃/叔丁基甲醚重结晶，得到产品3g。Add C16-1 (20mmol, 3.8g), 3-amino-5-methylpyrazole (24mmol, 2.4g), diisopropylethylamine (40mmol, 5.2g) and DMSO (30mL) to a 50mL reaction flask in sequence, The reaction was placed at 90°C for 16h under the protection of argon. TLC showed that the reaction was complete, water and ethyl acetate were added, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried and concentrated, and recrystallized from tetrahydrofuran/tert-butyl methyl ether to obtain 3 g of product.
2、C16-3的合成2. Synthesis of C16-3
氮气保护下，于100mL三口瓶中，依次加入C16-2(1g,4mmol)、C1-3(1.3g,4.4mmol)、Pd(PPh 3) 4(400mg,0.4mmol)、碳酸钾(1g,6mmol)、二氧六环(12mL)和水(3mL)，氮气置换三次，反应液在100℃搅拌16h，TLC和LC-MS显示反应完全，过滤后减压浓缩溶液，加水(20mL)稀释，乙酸乙酯萃取3次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，硅胶柱层析纯化(展开剂：二氯甲烷/甲醇＝30:1)得到产品700mg。 Under the protection of nitrogen, in a 100mL three-necked flask, add C16-2 (1g, 4mmol), C1-3 (1.3g, 4.4mmol), Pd(PPh 3 ) 4 (400mg, 0.4mmol), potassium carbonate (1g, 6mmol), dioxane (12mL) and water (3mL). Replace with nitrogen three times. The reaction solution was stirred at 100°C for 16h. TLC and LC-MS showed that the reaction was complete. After filtration, the solution was concentrated under reduced pressure and diluted with water (20mL). It was extracted with ethyl acetate three times, the organic phase was washed with saturated brine, the organic phase was dried, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (developing solvent: dichloromethane/methanol=30:1) to obtain 700 mg of the product.
3、C16-4的合成3. Synthesis of C16-4
50mL单口瓶中加入C16-3(690mg,1.6mmol)和乙醇(10mL)，小心加入10％Pd(OH) 2/C(300mg)，反应容器在氢气下置换3次，然后氢气保护下在50℃反应100h。LC-MS检测反应完毕，硅藻土缓慢过滤，用甲醇洗滤饼，滤液浓缩得产品650mg。 Add C16-3 (690mg, 1.6mmol) and ethanol (10mL) into a 50mL single-mouth flask, carefully add 10% Pd(OH) 2 /C (300mg), replace the reaction vessel 3 times under hydrogen, and then under the protection of hydrogen at 50 React at ℃ for 100h. LC-MS detected the completion of the reaction, slowly filtered through Celite, washed the filter cake with methanol, and concentrated the filtrate to obtain 650 mg of product.
4、C16-5的合成4. Synthesis of C16-5
50mL单口瓶中依次加入C16-4(540mg,1.1mmol)、甲醇(3mL)、THF(3mL)，H 2O(2mL)和LiOH(140mg,3.5mmol)，反应液在65℃搅拌16h。LC-MS检测反应完毕，减压浓缩，加入水(1mL)稀释，用***萃取杂质，水相用2M HCl调pH＝4-5，水相浓缩干燥得产品500mg，直接用于下一步。 C16-4 (540 mg, 1.1 mmol), methanol (3 mL), THF (3 mL), H 2 O (2 mL) and LiOH (140 mg, 3.5 mmol) were sequentially added to a 50 mL single-neck flask, and the reaction solution was stirred at 65° C. for 16 h. LC-MS detected the completion of the reaction, concentrated under reduced pressure, diluted with water (1 mL), extracted impurities with ether, the aqueous phase was adjusted to pH=4-5 with 2M HCl, and the aqueous phase was concentrated and dried to obtain 500 mg of product, which was used directly in the next step.
5、C16和C17的合成5. Synthesis of C16 and C17
10mL反应管中加入C16-5(307mg,0.83mmol)、HATU(253mg,1mmol)、二异丙基乙胺(0.7mL,5mmol)和DMF(6mL)，室温搅拌10min，然后加入C1-7(242mg,1mmol)，室温搅拌3h。TLC和LC-MS显示反应完毕，加入水(3mL)稀释，乙酸乙酯萃取3次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，柱层析纯化(DCM/MeOH＝10/1)得到顺反异构体，然后制备分离得到异构体C16(14mg)和C17(6mg)。Add C16-5 (307mg, 0.83mmol), HATU (253mg, 1mmol), diisopropylethylamine (0.7mL, 5mmol) and DMF (6mL) into the 10mL reaction tube, stir at room temperature for 10min, and then add C1-7( 242mg, 1mmol), stirred at room temperature for 3h. TLC and LC-MS showed that the reaction was complete, diluted with water (3mL), extracted with ethyl acetate 3 times, washed the organic phase with saturated brine, dried the organic phase, concentrated under reduced pressure to obtain the crude product, purified by column chromatography (DCM/MeOH=10 /1) Obtain cis-trans isomers, and then prepare and separate isomers C16 (14mg) and C17 (6mg).
C16(LC:T＝16.17min；purity:97.21％)C16(LC:T＝16.17min; purity:97.21%)
化合物C16的核磁分析数据：1H NMR(400MHz,Chloroform-d)δ8.40(d,J＝2.4Hz,1H),8.36(d,J＝4.5Hz,1H),7.89(d,J＝8.5Hz,1H),7.78(dd,J＝8.5,2.4Hz,1H),7.56(d,J＝4.4Hz,1H),7.35(d,J＝2.7Hz,1H),6.99(d,J＝2.9Hz,1H),6.91(s,1H),6.74(d,J＝7.9Hz,1H),5.26–5.16(m,1H),3.75(m,1H),3.24(m,3H),3.15(m,1H),2.42(s,3H),2.30(s,3H),1.98–1.62(m,8H),1.54(d,J＝7.0Hz,3H).NMR analysis data of compound C16: 1H NMR(400MHz,Chloroform-d)δ8.40(d,J=2.4Hz,1H), 8.36(d,J=4.5Hz,1H),7.89(d,J=8.5Hz ,1H),7.78(dd,J=8.5,2.4Hz,1H),7.56(d,J=4.4Hz,1H),7.35(d,J=2.7Hz,1H),6.99(d,J=2.9Hz ,1H),6.91(s,1H),6.74(d,J=7.9Hz,1H), 5.26-5.16(m,1H), 3.75(m,1H), 3.24(m,3H), 3.15(m, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 1.98-1.62 (m, 8H), 1.54 (d, J = 7.0 Hz, 3H).
C17(LC:T＝22.57min；purity:97.47％)C17 (LC: T = 22.57min; purity: 97.47%)
化合物C17的核磁分析数据：1H NMR(400MHz,Chloroform-d)δ8.49–8.28(m,1H),7.92(d,J＝8.5Hz,0H),7.77(dd,J＝8.5,2.4Hz,1H),7.58(d,J＝4.3Hz,0H),6.90–6.64(m,1H),6.12(s,1H),5.19(p,J＝7.3Hz,1H),3.78–3.67(m,1H),3.28(s,3H),3.14(m,1H),2.43(s,3H),2.32(s,3H),1.94–1.70(m,8H),1.57(d,J＝7.0Hz,2H).NMR analysis data of compound C17: 1H NMR(400MHz,Chloroform-d)δ8.49–8.28(m,1H),7.92(d,J=8.5Hz,0H),7.77(dd,J=8.5,2.4Hz, 1H), 7.58(d,J=4.3Hz,0H),6.90–6.64(m,1H),6.12(s,1H), 5.19(p,J=7.3Hz,1H),3.78–3.67(m,1H ), 3.28 (s, 3H), 3.14 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 1.94-1.70 (m, 8H), 1.57 (d, J = 7.0 Hz, 2H) .
实施例11Example 11
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000153
Figure PCTCN2020091425-appb-000153
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000154
Figure PCTCN2020091425-appb-000154
1、C18-1的合成1. Synthesis of C18-1
氮气保护下，于1L三口瓶中，依次加入C16-1(25g,133mmol)、N,N-二甲基甲酰胺二甲基缩醛(24g,200mmol)和异丙醇(300mL)，反应液在65℃搅拌16h，TLC和LC-MS显示反应完全，降至室温，过滤，滤饼用少量乙酸乙酯洗，过滤后减压浓缩得产品30g。Under the protection of nitrogen, in a 1L three-neck flask, add C16-1 (25g, 133mmol), N,N-dimethylformamide dimethyl acetal (24g, 200mmol) and isopropanol (300mL) in sequence, the reaction solution After stirring at 65°C for 16 hours, TLC and LC-MS showed that the reaction was complete, and the reaction was reduced to room temperature. The filter cake was washed with a small amount of ethyl acetate, filtered and concentrated under reduced pressure to obtain 30 g of the product.
2、C18-2的合成2. Synthesis of C18-2
250mL三口瓶中，加入C18-1(25g,91mmol)和浓盐酸(100mL)，反应液在45℃搅拌16h，降至室温，反应中加入冰水，过滤，滤饼用冰水和叔丁基甲醚洗得到粗品，硅胶柱层析纯化(展开剂：二氯甲烷/甲醇/氨水＝50:10:1)得到产品10g。Add C18-1 (25g, 91mmol) and concentrated hydrochloric acid (100mL) to a 250mL three-necked flask. The reaction solution was stirred at 45°C for 16h and cooled to room temperature. Ice water was added to the reaction, filtered, and the filter cake was iced water and tert-butyl methyl ether. The crude product was washed and purified by silica gel column chromatography (developing solvent: dichloromethane/methanol/ammonia water=50:10:1) to obtain 10 g of the product.
3、C18-3的合成3. Synthesis of C18-3
50mL三口瓶中，加入C18-2(2.4g,12mmol)和DMA(15mL)，在冰浴下分批加入NaH(0.576g，14.4mmol)，投料完毕后反应液在0℃到室温搅拌30分钟，加入对甲氧基苄氯(1.8g,15mmol)，反应液在室温搅拌16h，冰浴下缓慢滴加水(5mL)，乙酸乙酯萃取三次，有机相用饱和食盐水洗掉DMA，干燥有机相，减压浓缩得到粗品，硅胶柱层析纯化(展开剂：乙酸乙酯/石油醚＝1:10-1:1)得到产品2.5g。Add C18-2 (2.4g, 12mmol) and DMA (15mL) to a 50mL three-necked flask, add NaH (0.576g, 14.4mmol) in batches under ice bath, and stir the reaction solution at 0℃ to room temperature for 30 minutes , P-methoxybenzyl chloride (1.8g, 15mmol) was added, the reaction solution was stirred at room temperature for 16h, water (5mL) was slowly added dropwise in an ice bath, ethyl acetate was extracted three times, the organic phase was washed with saturated brine to remove DMA, and the organic phase was dried. The phase was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (developing solvent: ethyl acetate/petroleum ether=1:10-1:1) to obtain 2.5 g of the product.
4、C18-4的合成4. Synthesis of C18-4
氮气保护下，于100mL三口瓶中，依次加入原料C18-3(1.8g,5.4mmol)、C1-3(1.5g,5mmol)、Pd(PPh 3) 4(600mg,0.54mmol)、碳酸钾(1.8g,13mmol)、二氧六环(20mL)和水(4mL)，氮气置换三次，反应液在90℃搅拌16h，TLC和LC-MS显示反应完全，过滤后减压浓缩溶液，加水(20mL)稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，硅胶柱层析纯化(展开剂：乙酸乙酯/石油醚＝1:10-1:3)得到产品1.5g。 Under the protection of nitrogen, in a 100mL three-necked flask, add raw materials C18-3 (1.8g, 5.4mmol), C1-3 (1.5g, 5mmol), Pd(PPh 3 ) 4 (600mg, 0.54mmol), potassium carbonate ( 1.8g, 13mmol), dioxane (20mL) and water (4mL), replaced with nitrogen three times. The reaction solution was stirred at 90℃ for 16h. TLC and LC-MS showed that the reaction was complete. After filtration, the solution was concentrated under reduced pressure and water (20mL) ) Dilute, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, concentrate under reduced pressure to obtain the crude product, and purify by silica gel column chromatography (developing solvent: ethyl acetate/petroleum ether=1:10-1:3) 1.5 g of product was obtained.
5、C18-5的合成5. Synthesis of C18-5
氮气保护下，于50mL三口瓶中依次加入C18-4(1.1g,2.4mmol)、C1-17(700mg,3.6mmol)、Pd 2(dba) 3(210mg,0.24mmol)、DBU(727mg,4.8mmol)、t-BuXphos(210mg,0.25mmol)和乙二醇二甲醚(10mL)，氮气置换三次，反应液在60℃搅拌16h。TLC显示反应完全，过滤后减压浓缩溶液，加水(5mL)稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，硅胶柱层析纯化(展开剂：乙酸乙酯/石油醚＝1:10-1:3)得到产品900mg。 Under nitrogen protection, add C18-4 (1.1g, 2.4mmol), C1-17 (700mg, 3.6mmol), Pd 2 (dba) 3 (210mg, 0.24mmol), DBU (727mg, 4.8 mmol), t-BuXphos (210mg, 0.25mmol) and ethylene glycol dimethyl ether (10mL), replaced with nitrogen three times, and the reaction solution was stirred at 60°C for 16h. TLC showed that the reaction was complete. After filtration, the solution was concentrated under reduced pressure, diluted with water (5 mL), and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (developing solvent: Ethyl acetate/petroleum ether = 1:10-1:3) to obtain 900 mg of product.
6、C18-6的合成6. Synthesis of C18-6
50mL单口瓶中加入C18-5(500mg,0.8mmol)和乙醇(10mL)，小心加入10％Pd(OH) 2/C(300mg)，反应容器在氢气下置换三次，然后氢气保护下在65℃反应100h。LC-MS检测反应完毕，硅藻土缓慢过滤，用甲醇洗滤饼，滤液浓缩得粗品500mg。 Add C18-5 (500mg, 0.8mmol) and ethanol (10mL) into a 50mL single-neck flask, carefully add 10% Pd(OH) 2 /C (300mg), replace the reaction vessel three times under hydrogen, and then keep it at 65℃ under hydrogen protection Reaction for 100h. LC-MS detected the completion of the reaction, slowly filtered through Celite, washed the filter cake with methanol, and concentrated the filtrate to obtain 500 mg of crude product.
7、C18-7的合成7. Synthesis of C18-7
50mL单口瓶中依次加入C18-6(400mg,0.58mmol)和三氟乙酸(10mL)，反应液在80℃搅拌16h。LC-MS检测反应完毕，减压浓缩干燥得产品的三氟乙酸盐，直接用于下一步。C18-6 (400mg, 0.58mmol) and trifluoroacetic acid (10mL) were sequentially added to a 50mL single-mouth flask, and the reaction solution was stirred at 80°C for 16h. LC-MS detects the completion of the reaction, concentrates and dried under reduced pressure to obtain the trifluoroacetate of the product, which is directly used in the next step.
8、C18-8的合成8. Synthesis of C18-8
50mL单口瓶中依次加入C18-7(410mg,0.55mmol)、甲醇(3mL)、THF(3mL)、H 2O(2mL)和LiOH(230mg,5.5mmol)，反应液在65℃搅拌16h。LC-MS检测反应完毕，减压浓缩，加入水(5mL)稀释，用***萃取杂质，水相用2M HCl调pH＝4-5，水相浓缩干燥得粗品400mg，直接用于下一步。 C18-7 (410 mg, 0.55 mmol), methanol (3 mL), THF (3 mL), H 2 O (2 mL) and LiOH (230 mg, 5.5 mmol) were sequentially added to a 50 mL single-neck flask, and the reaction solution was stirred at 65°C for 16 h. LC-MS detected the completion of the reaction, concentrated under reduced pressure, diluted with water (5 mL), extracted impurities with ether, the aqueous phase was adjusted to pH=4-5 with 2M HCl, and the aqueous phase was concentrated and dried to obtain 400 mg of crude product, which was used directly in the next step.
9、C18和C19的合成9. Synthesis of C18 and C19
10mL反应管中加入C18-8(400mg,1.0mmol)、HATU(760mg,2mmol)、二异丙基乙胺(650mg,5mmol)和DMF(5mL)，室温搅拌10min，然后加入C1-7(320mg,1.2mmol)，室温搅拌16h。TLC和LC-MS显示反应完毕，加入水(3mL)稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品，柱层析纯化(DCM/MeOH＝20/1)得到顺反异构体190mg，通过制备分离得到100mg化合物C18和23mg化合物C19。Add C18-8 (400mg, 1.0mmol), HATU (760mg, 2mmol), diisopropylethylamine (650mg, 5mmol) and DMF (5mL) into a 10mL reaction tube, stir at room temperature for 10min, and then add C1-7 (320mg , 1.2mmol), stirred at room temperature for 16h. TLC and LC-MS showed that the reaction was complete, diluted with water (3mL), extracted three times with ethyl acetate, washed the organic phase with saturated brine, dried the organic phase, concentrated under reduced pressure to obtain the crude product, purified by column chromatography (DCM/MeOH=20/ 1) Obtain 190 mg of cis-trans isomer, and obtain 100 mg of compound C18 and 23 mg of compound C19 through preparation and separation.
化合物C18(LC:T＝30.51min；purity:98.18％)Compound C18 (LC: T = 30.51min; purity: 98.18%)
化合物C18的核磁分析数据：1H NMR(400MHz,Chloroform-d)δ8.41(s,1H),8.35(d,J＝4.6Hz,1H),7.88(d,J＝8.6Hz,1H),7.82–7.64(m,1H),7.56(d,J＝4.4Hz,1H),7.35(d,J＝2.7Hz,1H),7.09(td,J＝9.1,8.3,2.5Hz,1H),6.75(d,J＝11.8Hz,1H),6.09(s,1H),5.07–4.75(m,1H),4.13(s,1H),3.49(s,2H),3.23(s,3H),2.85(d,J＝7.7Hz,2H),2.68–2.46(m,1H),2.30(s,3H),2.04(m,4H),1.86(m,4H),1.56(d,J＝7.0Hz,3H).NMR analysis data of compound C18: 1H NMR(400MHz,Chloroform-d)δ8.41(s,1H),8.35(d,J=4.6Hz,1H),7.88(d,J=8.6Hz,1H),7.82 –7.64(m,1H),7.56(d,J=4.4Hz,1H),7.35(d,J=2.7Hz,1H),7.09(td,J=9.1,8.3,2.5Hz,1H),6.75( d,J=11.8Hz,1H), 6.09(s,1H), 5.07–4.75(m,1H), 4.13(s,1H), 3.49(s,2H), 3.23(s,3H), 2.85(d ,J=7.7Hz,2H),2.68–2.46(m,1H),2.30(s,3H),2.04(m,4H),1.86(m,4H),1.56(d,J=7.0Hz,3H) .
化合物C19(LC:T＝32.26min；purity:94.58％)Compound C19 (LC: T = 32.26min; purity: 94.58%)
化合物C19的核磁分析数据：1H NMR(400MHz,Chloroform-d)δ8.38(t,J＝4.3Hz,2H),7.90(d,J＝8.5Hz,1H),7.76(dd,J＝8.5,2.3Hz,1H),7.58(d,J＝4.3Hz,1H),6.87(d,J＝8.4Hz,1H),6.65(s,1H),6.08(s,1H),5.17(q,J＝7.3Hz,1H),4.15(m,1H),3.41(m,2H),3.30(s,3H),2.84(m,2H),2.31(s,3H),1.98-1.68(m,8H),1.55(d,J＝7.0Hz,3H).NMR analysis data of compound C19: 1H NMR (400MHz, Chloroform-d) δ 8.38 (t, J = 4.3 Hz, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5, 2.3Hz, 1H), 7.58 (d, J = 4.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H), 6.08 (s, 1H), 5.17 (q, J = 7.3Hz, 1H), 4.15 (m, 1H), 3.41 (m, 2H), 3.30 (s, 3H), 2.84 (m, 2H), 2.31 (s, 3H), 1.98-1.68 (m, 8H), 1.55(d,J=7.0Hz,3H).
实施例12Example 12
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000155
Figure PCTCN2020091425-appb-000155
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000156
Figure PCTCN2020091425-appb-000156
1、C20-1的合成1. Synthesis of C20-1
50mL单口瓶中依次加入C18-5(630mg,1mmol)和三氟乙酸(10mL)，反应液在20℃搅拌16h。LC-MS检测反应完毕，减压浓缩除去三氟乙酸，加入二氯甲烷(20mL)，有机相用饱和碳酸钠(5mL)洗，分离有机相，浓缩得粗产品420mg，直接用于下一步。C18-5 (630 mg, 1 mmol) and trifluoroacetic acid (10 mL) were sequentially added to a 50 mL single-neck flask, and the reaction solution was stirred at 20° C. for 16 h. LC-MS detected the completion of the reaction, concentrated under reduced pressure to remove trifluoroacetic acid, added dichloromethane (20 mL), washed the organic phase with saturated sodium carbonate (5 mL), separated the organic phase, concentrated to obtain 420 mg of crude product, which was used directly in the next step.
2、C20-2的合成2. Synthesis of C20-2
50mL单口瓶中加入C20-2(400mg,0.8mmol)和甲醇(10mL)，氮气氛围下小心加入10％Pd(OH) 2/C(100mg)，反应容器在氢气下置换三次，然后氢气保护下在50℃反应16h，降至室温，硅藻土缓慢过滤，用甲醇洗滤饼，滤液浓缩得到产品400mg。 Add C20-2 (400mg, 0.8mmol) and methanol (10mL) into a 50mL single-necked flask, carefully add 10% Pd(OH) 2 /C (100mg) under nitrogen atmosphere, and replace the reaction vessel three times under hydrogen, then under the protection of hydrogen After reacting at 50°C for 16 hours, the temperature was lowered to room temperature, and the diatomite was slowly filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain 400 mg of the product.
3、C20-3的合成3. Synthesis of C20-3
微波管中依次加入C20-2(400mg,0.8mmol)和三氟乙酸(3mL)，然后在140℃下微波反应15分钟。LC-MS检测反应完毕，减压浓缩干燥得产品的三氟乙酸盐300mg，粗品直接用于下一步。C20-2 (400mg, 0.8mmol) and trifluoroacetic acid (3mL) were sequentially added to the microwave tube, and then microwaved at 140°C for 15 minutes. LC-MS detects the completion of the reaction, concentrates and dried under reduced pressure to obtain 300 mg of trifluoroacetate, and the crude product is directly used in the next step.
4、C20-4的合成4. Synthesis of C20-4
50mL单口瓶中依次加入C20-3(300mg,0.58mmol)、甲醇(3mL)、THF(3mL)、H 2O(2mL)和LiOH.H 2O(170mg,4mmol)。反应液在65℃搅拌16h，LC-MS检测反应完毕，减压浓缩，加入水(1mL)稀释，用***萃取杂质，水相用2M HCl调pH＝4-5，水相浓缩干燥得310mg，直接用于下一步。 C20-3 (300 mg, 0.58 mmol), methanol (3 mL), THF (3 mL), H 2 O (2 mL) and LiOH.H 2 O (170 mg, 4 mmol) were sequentially added to a 50 mL single-mouth flask. The reaction solution was stirred at 65°C for 16 hours. LC-MS detected the completion of the reaction. It was concentrated under reduced pressure, diluted with water (1mL), and the impurities were extracted with ether. The aqueous phase was adjusted to pH 4-5 with 2M HCl, and the aqueous phase was concentrated and dried to obtain 310 mg. Used directly in the next step.
5、化合物C20和C21的合成5. Synthesis of compounds C20 and C21
10mL反应管中加入粗品C20-4(200mg,0.5mmol)、HATU(380mg,1mmol)、二异丙基乙胺(330mg,2.5mmol)和DMF(2mL)，室温搅拌10min，然后加入C1-7(160mg,0.6mmol)，室温搅拌16h。TLC和LC-MS显示反应完毕，加入水(3mL)稀释，乙酸乙酯萃取三次，有机相用饱和食盐水洗，干燥有机相，减压浓缩得到粗品180mg。粗品经制备分离得到13mg化合物C20和8mg化合物C21。Add crude C20-4 (200mg, 0.5mmol), HATU (380mg, 1mmol), diisopropylethylamine (330mg, 2.5mmol) and DMF (2mL) to a 10mL reaction tube, stir at room temperature for 10min, then add C1-7 (160mg, 0.6mmol), stirred at room temperature for 16h. TLC and LC-MS showed that the reaction was complete, diluted with water (3 mL), extracted three times with ethyl acetate, washed the organic phase with saturated brine, dried the organic phase, and concentrated under reduced pressure to obtain 180 mg of crude product. The crude product was prepared and separated to obtain 13 mg of compound C20 and 8 mg of compound C21.
实施例13Example 13
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000157
Figure PCTCN2020091425-appb-000157
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000158
Figure PCTCN2020091425-appb-000158
1、C22-2的合成1. Synthesis of C22-2
于250mL单口瓶中加入C22-1(5.0g，30.1mmol)、NCS(9.3g，70.4mmol)、DMF(100mL)，于25℃反应15h，倒入水中，用乙酸乙酯萃取三次，合并有机相，干燥浓缩柱层析(石油醚:乙酸乙酯＝10:1)得7.12g化合物C22-2，收率98％，[M+H]:221.1Add C22-1 (5.0g, 30.1mmol), NCS (9.3g, 70.4mmol), DMF (100mL) into a 250mL single-neck flask, react at 25℃ for 15h, pour into water, extract three times with ethyl acetate, and combine the organic Phase, dry and concentrated column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 7.12 g of compound C22-2, the yield is 98%, [M+H]: 221.1
化合物C22-2的核磁分析数据：1HNMR:(CDCl3,400Hz)δ7.65(s,1H),6.17(s,1H),3.93(s,3H)。Nuclear magnetic analysis data of compound C22-2: 1HNMR: (CDCl3, 400Hz) δ 7.65 (s, 1H), 6.17 (s, 1H), 3.93 (s, 3H).
2、C22-3的合成2. Synthesis of C22-3
于100mL小高压釜中加入C22-2(6.7g，30.1mmol)、氨水(wt％:20％)(50mL)EtOH(30mL)，于80℃反应15h，冷却到室温，旋干，加入饱和食盐水，乙酸乙酯萃取三次，合并有机相，干燥浓缩柱层析(PE:乙酸乙酯＝5:1)得4.25g化合物C22-3收率68％，[M+H]:206.1Add C22-2 (6.7g, 30.1mmol), ammonia (wt%: 20%) (50mL) EtOH (30mL) into a 100mL small autoclave, react at 80℃ for 15h, cool to room temperature, spin dry, add saturated salt Extract three times with water and ethyl acetate, combine the organic phases, dry and concentrate the column chromatography (PE: ethyl acetate = 5:1) to obtain 4.25 g of compound C22-3, the yield is 68%, [M+H]: 206.1
化合物C22-3的核磁分析数据：1HNMR:(MeOD,400Hz)δ7.52(s,1H)NMR analysis data of compound C22-3: 1HNMR: (MeOD,400Hz)δ7.52(s,1H)
3、C22-4的合成3. Synthesis of C22-4
于250mL小高压釜加入C22-3(3.8g，18.5mmol)、原甲酸三乙酯(80mL)于160℃反应7h，冷却到室温，旋干，加入饱和食盐水，乙酸乙酯萃取三次，合并有机相，甲基叔丁醚打浆得2.5g化合物C22-4收率64％，[M+H]:215.9Add C22-3 (3.8g, 18.5mmol) and triethyl orthoformate (80mL) to a 250mL small autoclave and react at 160℃ for 7h, cool to room temperature, spin dry, add saturated brine, extract three times with ethyl acetate, and combine The organic phase was beaten with methyl tert-butyl ether to obtain 2.5g of compound C22-4, the yield was 64%, [M+H]: 215.9
化合物C22-4的核磁分析数据：1HNMR:(DMSO-d6,400Hz)δ8.25(s,1H),7.92(s,1H)NMR analysis data of compound C22-4: 1HNMR: (DMSO-d6,400Hz)δ8.25(s,1H),7.92(s,1H)
4、C22-5的合成4. Synthesis of C22-5
于50mL单口瓶中加入C22-4(300mg，1.40mmol)、DMA(1mL)，置换氮气，在0℃加入钠氢(2.80mmol)再次置换氮气，滴加PMBCl(1.68mmol)于25℃ 反应12h，TLC监测反应结束，将反应液倒入水中，用乙酸乙酯萃取三次，合并有机相，干燥浓缩柱层析(石油醚:乙酸乙酯＝10:1)得347mg化合物C22-5，收率75％，[M+H]:336.0Add C22-4 (300mg, 1.40mmol) and DMA (1mL) to a 50mL single-neck flask, replace nitrogen, add sodium hydrogen (2.80mmol) at 0℃ to replace nitrogen again, add PMBCl (1.68mmol) dropwise and react at 25℃ for 12h , TLC monitored the completion of the reaction, the reaction solution was poured into water, extracted with ethyl acetate three times, the organic phases were combined, dried and concentrated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 347 mg of compound C22-5, yield 75%, [M+H]: 336.0
化合物C22-5的核磁分析数据：1HNMR:(CDCl3,400Hz)δ8.23(s,1H),8.06(s,1H),7.29(d,J＝8.8Hz,2H),6.89(d,J＝8.4Hz,2H),5.12(s,2H),3.79(s,3H).NMR analysis data of compound C22-5: 1HNMR: (CDCl3, 400Hz) δ8.23(s, 1H), 8.06(s, 1H), 7.29(d, J=8.8Hz, 2H), 6.89(d, J= 8.4Hz, 2H), 5.12 (s, 2H), 3.79 (s, 3H).
5、C22-6的合成5. Synthesis of C22-6
于50mL单口瓶中加入C22-5(347mg，1.04mmol)、1,4-二氧六环/H 2O(1mL/0.5mL)，加入C1-3(1.25mmol)、K 2CO 3(2.08mmol)、Pd(PPh 3) 4(0.052mmol)于100℃反应12h，TLC监测，反应结束，将反应液浓缩，加水(5mL)，用乙酸乙酯萃取三次，合并有机相，干燥浓缩柱层析(石油醚:乙酸乙酯＝5:1)得366mg化合物C22-6，收率75％，[M+H]:470.0。 Add C22-5 (347mg, 1.04mmol), 1,4-dioxane/H 2 O (1mL/0.5mL) into a 50mL single-mouth bottle, add C1-3 (1.25mmol), K 2 CO 3 (2.08 mmol), Pd(PPh 3 ) 4 (0.052 mmol) were reacted at 100°C for 12 hours, monitored by TLC, the reaction was completed, the reaction solution was concentrated, water (5mL) was added, extracted with ethyl acetate three times, the organic phases were combined, and the column layer was dried and concentrated After analysis (petroleum ether: ethyl acetate = 5:1), 366 mg of compound C22-6 was obtained, the yield was 75%, [M+H]: 470.0.
化合物C22-6的核磁分析数据：1HNMR:(CDCl3,400Hz)δ8.08(s,1H),7.97(s,1H),7.30(d,J＝8.8Hz,2H),6.88(d,J＝8.8Hz,2H),6.85(t,J＝2.4Hz,1H),5.11(s,2H),3.79(s,6H),3.32(s,3H),2.86(d,J＝2.0Hz,2H),2.86-2.79(m,2H),2.71-2.57(m,2H).NMR analysis data of compound C22-6: 1HNMR: (CDCl3, 400Hz) δ8.08(s, 1H), 7.97(s, 1H), 7.30(d, J=8.8Hz, 2H), 6.88(d, J= 8.8Hz, 2H), 6.85 (t, J = 2.4 Hz, 1H), 5.11 (s, 2H), 3.79 (s, 6H), 3.32 (s, 3H), 2.86 (d, J = 2.0 Hz, 2H) , 2.86-2.79 (m, 2H), 2.71-2.57 (m, 2H).
6、C22-7的合成6. Synthesis of C22-7
于50mL单口瓶中加入C22-6(1.01g，2.15mmol)、1,4-二氧六环(10mL)，在氮气保护下加入C1-17(2.58mmol)、AcOK(4.30mmol)、Pd 2(dba) 3(0.11mmol)、t-Buxphos(0.11mmol)，于90℃反应12h，TLC监测，反应结束，将反应液浓缩，加水(5mL)，用乙酸乙酯萃取三次，合并有机相，干燥浓缩柱层析(石油醚:乙酸乙酯＝5:1)得761mg化合物C22-7，收率56％，[M+H]:631.3。 Add C22-6 (1.01g, 2.15mmol), 1,4-dioxane (10mL) to a 50mL single-mouth flask, and add C1-17 (2.58mmol), AcOK (4.30mmol), Pd 2 under nitrogen protection (dba) 3 (0.11mmol), t-Buxphos (0.11mmol), react at 90°C for 12h, monitored by TLC, the reaction is over, the reaction solution is concentrated, water (5mL) is added, extracted with ethyl acetate three times, and the organic phases are combined. Dry and concentrated column chromatography (petroleum ether: ethyl acetate = 5:1) gave 761 mg of compound C22-7 with a yield of 56%, [M+H]: 631.3.
化合物C22-7的核磁分析数据：1HNMR:(CDCl3,400Hz)δ7.89(s,1H),7.77(s,1H),7.31(d,J＝4.0Hz,2H),7.28(s,1H),6.86(d,J＝8.8Hz,2H),6.72(s,1H),6.41(s,1H),5.09(s,2H),3.80(s,6H),3.34(s,3H),2.86(d,J＝2.0Hz,2H),2.81-2.60(m,2H),2.54(s,3H),2.44-2.14(m,2H),1.67(s,9H).NMR analysis data of compound C22-7: 1HNMR: (CDCl3,400Hz)δ7.89(s,1H),7.77(s,1H),7.31(d,J=4.0Hz,2H),7.28(s,1H) ,6.86(d,J=8.8Hz,2H),6.72(s,1H),6.41(s,1H),5.09(s,2H),3.80(s,6H),3.34(s,3H),2.86( d,J=2.0Hz,2H),2.81-2.60(m,2H),2.54(s,3H),2.44-2.14(m,2H),1.67(s,9H).
7、C22-8的合成7. Synthesis of C22-8
于50mL单口瓶中加入C22-7(751mg，1.19mmol)、乙酸乙酯(10mL)，在氮气保护下加入Pd/C(0.12mmol)，再次置换氮气，氢气条件下，室温反应12h，TLC监测反应结束，将反应液过滤，合并有机相，干燥浓缩得638mg化合物C22-8，收率85％，[M+H]:533.3。Add C22-7 (751mg, 1.19mmol) and ethyl acetate (10mL) into a 50mL single-mouth flask, add Pd/C (0.12mmol) under the protection of nitrogen, and replace the nitrogen again. Under hydrogen conditions, react at room temperature for 12h, monitored by TLC After the reaction, the reaction solution was filtered, the organic phases were combined, dried and concentrated to obtain 638 mg of compound C22-8 with a yield of 85%, [M+H]: 533.3.
8、C22-9的合成8. Synthesis of C22-9
于50mL单口瓶中加入C22-8(217mg，0.34mmol)、三氟乙酸(5mL)，90℃反应18h，TLC监测，反应结束，将反应液浓缩得143mg化合物C22-9，收率100％，[M+H]:413.1。C22-8 (217mg, 0.34mmol) and trifluoroacetic acid (5mL) were added to a 50mL single-neck flask, reacted at 90°C for 18h, monitored by TLC, and the reaction was completed. The reaction solution was concentrated to obtain 143mg of compound C22-9 with a yield of 100%. [M+H]: 413.1.
9、C22-10的合成9. Synthesis of C22-10
于25mL单口瓶中加入C22-9(139mg，0.34mmol)、LiOH·H 2O(1.3mmol)、 MeOH/H 2O(2mL/0.4mL)，将反应置于60℃反应18h。LC-MS显示反应完毕，浓缩反应液得到粗品229mg,[M+H]:399.1。 C22-9 (139 mg, 0.34 mmol), LiOH·H 2 O (1.3 mmol), MeOH/H 2 O (2 mL/0.4 mL) were added to a 25 mL single-mouth flask, and the reaction was placed at 60° C. for 18 h. LC-MS showed that the reaction was complete, and the reaction solution was concentrated to obtain crude product 229mg, [M+H]:399.1.
10、C22和C23的合成10. Synthesis of C22 and C23
于25mL单口瓶中加入C22-10(320mg，0.80mmol)、C1-7(0.88mmol)、DMF(2mL)、三乙胺(1.60mmol)和PyBOP(1.20mmol)室温反应18h。LC-MS显示反应完毕，将反应液倒入10mL水中，乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，浓缩得粗品，粗品制备分离得15mg化合物C22，[M+H]:587.3和8mg化合物C23，[M+H]:587.3。C22-10 (320mg, 0.80mmol), C1-7 (0.88mmol), DMF (2mL), triethylamine (1.60mmol) and PyBOP (1.20mmol) were added to a 25mL single-necked flask to react at room temperature for 18h. LC-MS showed that the reaction was complete, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was prepared and separated to obtain 15 mg of compound C22, [M+H]: 587.3 and 8 mg of compound C23, [M+H]: 587.3.
实施例14Example 14
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000159
Figure PCTCN2020091425-appb-000159
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000160
Figure PCTCN2020091425-appb-000160
1、C24-2的合成1. Synthesis of C24-2
将化合物C1-8(1.0g,5.03mmol)和化合物C24-1(0.62g,6.03mmol)溶于DMF(10ml)中，然后加入碳酸钾(1.6g,11.57mmol)，升温至120℃搅拌过夜。待反应结束后冷却至室温，减压浓缩除去溶剂DMF，然后用乙酸乙酯稀释。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得到0.5g化合物C24-2。Dissolve compound C1-8 (1.0g, 5.03mmol) and compound C24-1 (0.62g, 6.03mmol) in DMF (10ml), then add potassium carbonate (1.6g, 11.57mmol), heat to 120°C and stir overnight . After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent DMF, and then diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 0.5 g of compound C24-2.
化合物C24-2的核磁分析数据：1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.09(s,1H),8.57-8.55(t,1H),7.97-7.95(d,1H,J＝8.58Hz),2.68(s,3H).NMR analysis data of compound C24-2: 1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.09(s,1H),8.57-8.55(t,1H),7.97-7.95(d,1H) ,J=8.58Hz), 2.68(s, 3H).
2、C24-3的合成2. Synthesis of C24-3
将化合物C24-2(397mg,1.79mmol)和R-(+)-叔丁基亚磺酰胺(260mg, 2.15mmol)溶于干燥的四氢呋喃(20mL)中，然后加入钛酸四乙酯(898mg,3.94mmol)，氮气保护下，升温至70℃搅拌过夜。待反应结束后冷却至室温，加入1mL水，减压过滤，滤液用乙酸乙酯萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到429mg化合物C24-3.Compound C24-2 (397mg, 1.79mmol) and R-(+)-tert-butylsulfinamide (260mg, 2.15mmol) were dissolved in dry tetrahydrofuran (20mL), and then tetraethyl titanate (898mg, 3.94mmol), heated to 70°C and stirred overnight under the protection of nitrogen. After the reaction was completed, it was cooled to room temperature, 1 mL of water was added, filtered under reduced pressure, and the filtrate was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 429 mg of compound C24-3.
化合物C24-3的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.54(s,1H),9.02-9.01(d,1H,J＝1.93Hz),8.55-8.52(dd,1H,J＝8.60Hz,2.68Hz),7.94-7.92(d,1H,J＝8.35Hz),2.80(s,3H),1.25(s,9H). NMR analysis data of compound C24-3: 1 H NMR (400MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 9.02-9.01 (d, 1H, J=1.93 Hz), 8.55-8.52 (dd, 1H) ,J＝8.60Hz,2.68Hz),7.94-7.92(d,1H,J＝8.35Hz), 2.80(s,3H),1.25(s,9H).
3、C24-4的合成3. Synthesis of C24-4
将化合物C24-3(429mg,1.32mmol)溶于干燥的四氢呋喃(5mL)中，氮气保护下，降温至-78℃滴加1M三仲丁基硼氢化锂的四氢呋喃溶液(3.96ml,3.96mmol)，并保持-78℃搅拌1h，TLC检测反应结束后，滴加甲醇淬灭，升至室温，用乙酸乙酯稀释。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到362mg化合物C24-4.Dissolve compound C24-3 (429mg, 1.32mmol) in dry tetrahydrofuran (5mL), under the protection of nitrogen, lower the temperature to -78°C and add 1M lithium tri-sec-butylborohydride solution in tetrahydrofuran (3.96ml, 3.96mmol) dropwise , And stirring at -78°C for 1 h. After the reaction was detected by TLC, methanol was added dropwise to quench, the temperature was raised to room temperature, and it was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 362 mg of compound C24-4.
化合物C24-4的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.50(s,1H),8.59-8.58(d,1H,J＝1.93Hz),8.13-8.11(dd,1H,J＝8.65Hz,2.34Hz),7.88-7.85(d,1H,J＝8.65Hz),5.69-5.68(d,1H,J＝5.67Hz),4.68-4.61(m,1H),1.58-1.57(d,3H,J＝6.80Hz),1.17(s,9H). NMR analysis data of compound C24-4: 1 H NMR (400MHz, DMSO-d 6 ) δ 9.50 (s, 1H), 8.59-8.58 (d, 1H, J=1.93 Hz), 8.13-8.11 (dd, 1H) ,J=8.65Hz,2.34Hz),7.88-7.85(d,1H,J=8.65Hz), 5.69-5.68(d,1H,J=5.67Hz), 4.68-4.61(m,1H), 1.58-1.57 (d, 3H, J = 6.80 Hz), 1.17 (s, 9H).
4、C24-5的合成4. Synthesis of C24-5
将化合物C24-4(362mg,1.11mmol)溶于二氧六环(1.4ml)和无水甲醇(1.4ml)的混合溶液中，然后加入的4M氯化氢的二氧六环溶液(2.8ml)，室温搅拌2h，然后加入甲基叔丁基醚，过滤，干燥得到258mg化合物C24-5。Compound C24-4 (362mg, 1.11mmol) was dissolved in a mixed solution of dioxane (1.4ml) and anhydrous methanol (1.4ml), and then 4M hydrogen chloride in dioxane solution (2.8ml) was added, Stir at room temperature for 2 hours, then add methyl tert-butyl ether, filter and dry to obtain 258 mg of compound C24-5.
化合物C24-5的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.50(s,1H),8.73-8.71(m,4H),8.29-8.26(dd,1H,J＝8.55Hz,2.39Hz),7.93-7.91(d,1H,J＝8.30Hz),4.61(br,1H),1.60-1.58(d,3H,J＝7.14Hz). NMR analysis data of compound C24-5: 1 H NMR (400MHz, DMSO-d 6 ) δ 9.50 (s, 1H), 8.73-8.71 (m, 4H), 8.29-8.26 (dd, 1H, J = 8.55 Hz ,2.39Hz),7.93-7.91(d,1H,J＝8.30Hz), 4.61(br,1H),1.60-1.58(d,3H,J＝7.14Hz).
5、C24和C25的合成5. Synthesis of C24 and C25
将化合物C24-5(40mg，0.16mmol)和化合物C3-19(60mg，0.16mmol)溶于DMF(1.2ml)中，加入DIPEA(160mg，1.24mmol)，室温搅拌5min后，再加入HATU(88mg，0.23mmol)，然后室温搅拌1h。将反应液用乙酸乙酯稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经Prep-HPLC纯化得到31mg化合物C24和27mg化合物C25。Compound C24-5 (40mg, 0.16mmol) and compound C3-19 (60mg, 0.16mmol) were dissolved in DMF (1.2ml), DIPEA (160mg, 1.24mmol) was added, and after stirring at room temperature for 5 min, HATU (88mg , 0.23mmol), and then stirred at room temperature for 1h. The reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 31 mg of compound C24 and 27 mg of compound C25.
化合物C24的核磁分析数据： 1H NMR(400MHz,CDCl 3)δ9.05(s,1H),8.67-8.66(d,1H,J＝3.99Hz,1.54Hz),8.44-8.43(d,1H,J＝1.94Hz),7.91-7.89(dd,1H,J＝8.45Hz,1.41Hz),7.86-7.79(m,2H),7.38-7.35(m,2H),7.06(s,1H)，6.93-6.91(d,1H,J＝7.75Hz),5.88(s,1H)，5.22-5.18(m,1H),4.24-4.18(m,1H),3.31(s,3H),2.32(s,3H),2.18-2.10(m,2H),2.07-1.94(m,5H),1.91-1.86(m,2H),1.59-1.57(d,3H,J＝7.04Hz). NMR analysis data of compound C24: 1 H NMR (400MHz, CDCl 3 ) δ9.05 (s, 1H), 8.67-8.66 (d, 1H, J = 3.99 Hz, 1.54 Hz), 8.44 to 8.43 (d, 1H, J = 1.94 Hz), 7.91-7.89 (dd, 1H, J = 8.45 Hz, 1.41 Hz), 7.86-7.79 (m, 2H), 7.38-7.35 (m, 2H), 7.06 (s, 1H), 6.93 6.91(d,1H,J=7.75Hz),5.88(s,1H),5.22-5.18(m,1H),4.24-4.18(m,1H),3.31(s,3H),2.32(s,3H) ,2.18-2.10(m,2H),2.07-1.94(m,5H),1.91-1.86(m,2H),1.59-1.57(d,3H,J=7.04Hz).
化合物C25的核磁分析数据： 1H NMR(400MHz,CDCl 3)δ8.99(s,1H),8.59-8.58(dd, 1H,J＝3.88Hz,1.55Hz),8.43-8.42(d,1H,J＝2.07Hz),7.85-7.79(m,1H),7.74-7.72(m,1H),7.30-7.27(m,3H),6.75-6.73(d,1H,J＝7.49Hz),5.79(s,1H)，5.19-5.14(m,1H),4.19-4.14(m,1H),3.21(s,3H),2.34-2.30(m,1H),2.24(s,1H),2.22-2.11(m,3H),1.98-1.92(m,3H),1.78-1.71(m,2H),1.53-1.51(d,3H,J＝7.23Hz). NMR analysis data of compound C25: 1 H NMR (400MHz, CDCl 3 )δ8.99(s,1H), 8.59-8.58(dd, 1H,J=3.88Hz,1.55Hz), 8.43-8.42(d,1H, J = 2.07Hz), 7.85-7.79 (m, 1H), 7.74-7.72 (m, 1H), 7.30-7.27 (m, 3H), 6.75-6.73 (d, 1H, J = 7.49 Hz), 5.79 (s ,1H), 5.19-5.14(m,1H),4.19-4.14(m,1H),3.21(s,3H),2.34-2.30(m,1H),2.24(s,1H),2.22-2.11(m ,3H),1.98-1.92(m,3H),1.78-1.71(m,2H),1.53-1.51(d,3H,J=7.23Hz).
实施例15Example 15
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000161
Figure PCTCN2020091425-appb-000161
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000162
Figure PCTCN2020091425-appb-000162
1、C26-2的合成1. Synthesis of C26-2
50mL单口瓶中加入C26-1(1.57g，10mmol)、4-氟-1H吡唑(860mg，10mmol)、N,N-二甲基甲酰胺(10mL)、碳酸钾(2.76g，20mmol)，将反应置于100℃下反应8h。LC-MS显示反应完毕，搅拌下将反应液倒入水(200mL)中有固体析出，过滤，水洗滤饼，将滤饼干燥，得固体1.08g。[M+1]:207.03。Add C26-1 (1.57g, 10mmol), 4-fluoro-1H pyrazole (860mg, 10mmol), N,N-dimethylformamide (10mL), potassium carbonate (2.76g, 20mmol) into a 50mL single-mouth flask, The reaction was placed at 100°C for 8h. LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (200 mL), and solids precipitated. After filtration, the filter cake was washed with water, and the filter cake was dried to obtain 1.08 g of solid. [M+1]:207.03.
2、C26-3的合成2. Synthesis of C26-3
100mL单口瓶中依次加入C26-2(870mg,4.2mmol)、R-叔丁基亚磺酰胺(560mg,4.63mmol)、钛酸四乙酯(1.92g,8.4mmol)、干燥四氢呋喃(10mL)，将反应置于75℃下反应过夜。冷却，加水(30mL)稀释，抽滤，滤液用乙酸乙酯(20mL)萃取三次，无水硫酸钠干燥有机相，减压蒸干，柱层析得产品500mg。Add C26-2 (870mg, 4.2mmol), R-tert-butylsulfinamide (560mg, 4.63mmol), tetraethyl titanate (1.92g, 8.4mmol), and dry tetrahydrofuran (10mL) in a 100mL single-necked flask. The reaction was placed at 75°C overnight. Cool, dilute with water (30 mL), filter with suction, extract the filtrate with ethyl acetate (20 mL) three times, dry the organic phase with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and obtain 500 mg of product by column chromatography.
3、C26-4的合成3. Synthesis of C26-4
50mL单口瓶中依次加入C26-3(100mg,0.32mmol)、干燥四氢呋喃(2mL)，降温至-78℃，滴加三仲丁基硼氢化锂(0.7mL,0.7mmol，1.0M)，于-78℃下反应1h，-60℃下加甲醇(1mL)淬灭反应，加水(5mL)稀释，用乙酸乙酯(5mL)萃取三次，干燥有机相，减压蒸干，柱层析得产物113mg。Add C26-3 (100mg, 0.32mmol) and dry tetrahydrofuran (2mL) to a 50mL single-necked flask in turn, cool to -78℃, and add lithium tri-sec-butylborohydride (0.7mL, 0.7mmol, 1.0M) dropwise to- React at 78°C for 1 hour, add methanol (1mL) at -60°C to quench the reaction, dilute with water (5mL), extract three times with ethyl acetate (5mL), dry the organic phase, evaporate to dryness under reduced pressure, and column chromatography to obtain the product 113mg .
化合物C26-4的核磁分析数据：1H NMR(400MHz,CDCl3)δ9.23(d,J＝1.4Hz, 1H),8.36(d,J＝1.5Hz,1H),8.33(d,J＝4.6Hz,1H),7.66(d,J＝4.3Hz,1H),4.77(p,J＝6.6Hz,1H),3.74(d,J＝5.9Hz,1H),1.67(d,J＝6.8Hz,3H),1.22(s,9H)。NMR analysis data of compound C26-4: 1H NMR(400MHz,CDCl3)δ9.23(d,J=1.4Hz, 1H), 8.36(d,J=1.5Hz,1H), 8.33(d,J=4.6Hz ,1H),7.66(d,J=4.3Hz,1H),4.77(p,J=6.6Hz,1H), 3.74(d,J=5.9Hz,1H),1.67(d,J=6.8Hz,3H ), 1.22(s, 9H).
4、C26-5的合成4. Synthesis of C26-5
50mL单口瓶中依次加入C26-4(100mg，0.32mmol)、二氯甲烷(3mL)，甲醇(0.5mL)、HCl/dioxane(4M,1.5mL)将反应置于室温下反应3h。LC-MS检测反应完全，加二氯甲烷稀释，过滤，乙酸乙酯洗涤滤饼，干燥滤饼得产物67mg。[M+1]:208.06。C26-4 (100mg, 0.32mmol), dichloromethane (3mL), methanol (0.5mL), HCl/dioxane (4M, 1.5mL) were sequentially added to a 50mL single-necked flask, and the reaction was placed at room temperature for 3h. LC-MS detected that the reaction was complete, diluted with dichloromethane, filtered, washed the filter cake with ethyl acetate, and dried the filter cake to obtain 67 mg of the product. [M+1]:208.06.
5、C26的合成5. Synthesis of C26
25mL单口瓶中加入C26-5(47mg，0.17mmol)、C3-19(65mg，0.17mmol)，N,N-二甲基甲酰胺(1mL)、N,N-二异丙基乙胺(175mg，1.36mmol)室温搅拌5min，加入HATU(97mg，0.26mmol)反应于室温下反应30min。LC-MS显示反应完毕，将反应液倒入10mL水中过滤得粗品，制备分离得C26(37.6mg，purity:91％)，[M+1]:571.3。Add C26-5 (47mg, 0.17mmol), C3-19 (65mg, 0.17mmol), N,N-dimethylformamide (1mL), N,N-diisopropylethylamine (175mg , 1.36 mmol) was stirred at room temperature for 5 min, HATU (97 mg, 0.26 mmol) was added and the reaction was carried out at room temperature for 30 min. LC-MS showed that the reaction was complete, the reaction solution was poured into 10 mL of water and filtered to obtain a crude product, which was prepared and isolated to obtain C26 (37.6 mg, purity: 91%), [M+1]: 571.3.
化合物C26的核磁分析数据：1H NMR(400MHz,DMSO-d6)δ11.76(d,J＝5.3Hz,1H),9.14(dd,J＝6.8,3.1Hz,2H),8.79–8.68(m,1H),8.63(tt,J＝4.2,2.0Hz,1H),8.54(d,J＝5.3Hz,1H),8.45(t,J＝6.4Hz,1H),8.12–7.97(m,2H),7.73–7.43(m,2H),6.08–5.93(m,1H),5.16(q,J＝7.1Hz,1H),3.27–3.16(m,3H),2.28–2.17(m,3H),2.12–1.64(m,9H),1.51(d,J＝6.8Hz,3H).NMR analysis data of compound C26: 1H NMR(400MHz,DMSO-d6)δ11.76(d,J=5.3Hz,1H), 9.14(dd,J=6.8,3.1Hz,2H), 8.79-8.68(m, 1H), 8.63(tt,J=4.2,2.0Hz,1H), 8.54(d,J=5.3Hz,1H), 8.45(t,J=6.4Hz,1H), 8.12–7.97(m,2H), 7.73–7.43(m,2H), 6.08–5.93(m,1H), 5.16(q,J=7.1Hz,1H), 3.27–3.16(m,3H), 2.28–2.17(m,3H), 2.12– 1.64(m,9H),1.51(d,J=6.8Hz,3H).
实施例16Example 16
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000163
Figure PCTCN2020091425-appb-000163
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000164
Figure PCTCN2020091425-appb-000164
1、C27-3的合成1. Synthesis of C27-3
将化合物C27-1(1.49g,10mmol)和Pd(PPh 3) 4(115mg,0.1mmol)溶于甲苯 (50mL)中，然后加入化合物C27-2(4.33g,12mmol)，升温至120℃搅拌5h。待反应结束后冷却至室温，加入1M HCl(20mL)升温至60℃搅拌1h，浓缩，加水然后用乙酸乙酯稀释。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得到1.2g化合物C27-3。 Compound C27-1 (1.49g, 10mmol) and Pd(PPh 3 ) 4 (115mg, 0.1mmol) were dissolved in toluene (50mL), then compound C27-2 (4.33g, 12mmol) was added, heated to 120°C and stirred 5h. After the reaction was completed, it was cooled to room temperature, 1M HCl (20 mL) was added, and the temperature was raised to 60° C. and the mixture was stirred for 1 h, concentrated, and then diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.2 g of compound C27-3.
化合物C27-3的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.12-8.10(d,1H,J＝9.04Hz),7.69-7.67(d,1H,J＝9.04Hz),2.88(s,J＝3H).NMR analysis data of compound C27-3: 1H NMR (400MHz, CDCl3) δ8.12-8.10 (d, 1H, J = 9.04 Hz), 7.69-7.67 (d, 1H, J = 9.04 Hz), 2.88 (s, J=3H).
2、C27-4的合成2. Synthesis of C27-4
将化合物C27-3(500mg,3.2mmol)和4氟-1H吡唑(303mg,3.5mmol)溶于DMF(10mL)中，然后加入碳酸钾(1020mg,7.4mmol)，升温至100℃搅拌过夜。待反应结束后冷却至室温，浓缩，加水后乙酸乙酯萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得到440mg化合物C27-4.Compound C27-3 (500 mg, 3.2 mmol) and 4fluoro-1H pyrazole (303 mg, 3.5 mmol) were dissolved in DMF (10 mL), then potassium carbonate (1020 mg, 7.4 mmol) was added, and the temperature was raised to 100°C and stirred overnight. After the reaction is over, it is cooled to room temperature, concentrated, and water is added and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 440 mg of compound C27-4.
化合物C27-4的核磁分析数据：1H NMR(400MHz,DMSO-d6)δ9.08-9.07(dd,1H,J＝4.60Hz，0.62Hz),8.36-8.34(d,1H,J＝9.04Hz),8.31-8.28(d,1H,J＝9.04Hz),8.20-8.18(dd,1H,J＝4.10Hz,0.75Hz),2.79(s,3H).NMR analysis data of compound C27-4: 1H NMR(400MHz,DMSO-d6)δ9.08-9.07(dd,1H,J＝4.60Hz,0.62Hz),8.36-8.34(d,1H,J＝9.04Hz) , 8.31-8.28(d,1H,J=9.04Hz), 8.20-8.18(dd,1H,J=4.10Hz,0.75Hz), 2.79(s,3H).
3、C27-5的合成3. Synthesis of C27-5
将化合物C27-4(350mg,1.7mmol)和R-叔丁基亚磺酰胺(247mg,2.0mmol)溶于干燥的四氢呋喃(40mL)中，加入钛酸四乙酯(775mg,3.4mmol)氮气保护下，升温至80℃搅拌过夜，加入1mL水，过滤，滤饼乙酸乙酯洗涤，滤液浓缩，柱层析纯化，得到342mg化合物C27-5.Compound C27-4 (350 mg, 1.7 mmol) and R-tert-butylsulfinamide (247 mg, 2.0 mmol) were dissolved in dry tetrahydrofuran (40 mL), and tetraethyl titanate (775 mg, 3.4 mmol) was added under nitrogen protection The temperature was raised to 80°C and stirred overnight, 1mL of water was added, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and purified by column chromatography to obtain 342mg of compound C27-5.
化合物C27-5的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.66-8.65(d,1H J＝4.53Hz),8.35-8.33(d,1H,J＝9.04Hz),8.24-8.22(d,1H,J＝9.04Hz),7.73-7.72(d,1H,J＝4.21Hz),3.02(s,3H),1.35(s,9H).NMR analysis data of compound C27-5: 1H NMR(400MHz, CDCl3)δ8.66-8.65(d,1HJ=4.53Hz),8.35-8.33(d,1H,J=9.04Hz),8.24-8.22(d ,1H,J＝9.04Hz),7.73-7.72(d,1H,J＝4.21Hz),3.02(s,3H),1.35(s,9H).
4、C27-6的合成4. Synthesis of C27-6
将化合物C27-5(292mg,0.94mmol)溶于干燥的四氢呋喃(3mL)，降温至-78℃，滴加三仲丁基硼氢化锂(2.83mL,2.83mmol，1.0M)，于-78℃下反应1h，-60℃下加甲醇(3mL)淬灭反应，加水稀释，用乙酸乙酯萃取，干燥有机相，减压蒸干，柱层析得产物200mg。Compound C27-5 (292mg, 0.94mmol) was dissolved in dry tetrahydrofuran (3mL), the temperature was reduced to -78℃, and lithium tri-sec-butylborohydride (2.83mL, 2.83mmol, 1.0M) was added dropwise at -78℃ After reacting for 1 h, the reaction was quenched by adding methanol (3 mL) at -60°C, diluting with water, extracting with ethyl acetate, drying the organic phase, evaporating to dryness under reduced pressure, and column chromatography to obtain 200 mg of the product.
化合物C27-6的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.55-8.54(dd,1H J＝4.61Hz，0.55Hz),8.12-8.09(d,1H,J＝9.04Hz),7.62-7.60(m,2H),4.88-4.85(m,1H),1.66-1.64(d,3H,J＝6.95Hz),1.16(s,9H).NMR analysis data of compound C27-6: 1H NMR (400MHz, CDCl3) δ8.55-8.54 (dd, 1H J = 4.61Hz, 0.55Hz), 8.12-8.09 (d, 1H, J = 9.04Hz), 7.62 7.60 (m, 2H), 4.88-4.85 (m, 1H), 1.66-1.64 (d, 3H, J = 6.95 Hz), 1.16 (s, 9H).
5、C27-7的合成5. Synthesis of C27-7
将化合物C27-6(200mg,0.71mmol)溶于二氧六环(1.8mL)和甲醇(1.8mL)中，加入4M盐酸/二氧六环(1.8mL,7.2mmol),室温反应3h，LC-MS检测反应完全，加乙酸乙酯稀释，过滤，乙酸乙酯洗涤滤饼，干燥滤饼得产物47mg。Compound C27-6 (200mg, 0.71mmol) was dissolved in dioxane (1.8mL) and methanol (1.8mL), added 4M hydrochloric acid/dioxane (1.8mL, 7.2mmol), reacted at room temperature for 3h, LC -MS detected that the reaction was complete, diluted with ethyl acetate, filtered, washed the filter cake with ethyl acetate, and dried the filter cake to obtain 47 mg of the product.
化合物C27-7的核磁分析数据：1H NMR(400MHz,DMSO-d6)δ8.98-8.97(dd,1H, J＝4.54Hz，0.62Hz),8.81(br,3H),8.34-8.32(d,1H,J＝9.25Hz),8.14-8.10(m,2H),4.83-4.77(m,1H),1.62-1.60(d,3H,J＝7.66Hz).NMR analysis data of compound C27-7: 1H NMR(400MHz,DMSO-d6)δ8.98-8.97(dd,1H, J=4.54Hz,0.62Hz),8.81(br,3H),8.34-8.32(d, 1H, J = 9.25 Hz), 8.14-8.10 (m, 2H), 4.83-4.77 (m, 1H), 1.62-1.60 (d, 3H, J = 7.66 Hz).
6、C27和C28的合成6. Synthesis of C27 and C28
将化合物C27-7(30mg,0.12mmol)和化合物C3-19(48mg,0.12mmol)溶于1mL DMF中，加入二异丙基乙胺(0.3mL,0.96mmol)，室温搅拌5min，再加入HATU(71mg,0.18mmol)，然后室温搅拌1h。将反应液用乙酸乙酯稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经制备液相分离得到20mg化合物C27和10mg化合物C28.Dissolve compound C27-7 (30mg, 0.12mmol) and compound C3-19 (48mg, 0.12mmol) in 1mL DMF, add diisopropylethylamine (0.3mL, 0.96mmol), stir at room temperature for 5min, then add HATU (71mg, 0.18mmol), then stirred at room temperature for 1h. The reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated into liquid phase to obtain 20mg compound C27 and 10mg compound C28.
化合物C27的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.58-8.56(dd,1H,J＝4.06Hz,1.72Hz),8.53-8.52(d,1H,J＝4.84Hz),8.09-8.07(d,1H,J＝9.37Hz),7.86-7.84(d,1H,J＝8.12Hz),7.81-7.88(dd,1H,J＝8.74Hz,1.56Hz),7.61-7.57(m,2H),7.33(br,1H),7.28-7.25(m,1H),7.22(s,1H),5.89(br,1H),5.34-5.28(m,1H),4.13-4.09(m,1H),3.27(s,3H),2.27(s,3H),2.15-1.76(m,8H),1.62-1.59(d,3H,J＝6.87Hz).NMR analysis data of compound C27: 1H NMR (400MHz, CDCl3) δ8.58-8.56(dd,1H,J=4.06Hz,1.72Hz),8.53-8.52(d,1H,J=4.84Hz),8.09-8.07 (d, 1H, J = 9.37 Hz), 7.86-7.84 (d, 1H, J = 8.12 Hz), 7.81-7.88 (dd, 1H, J = 8.74 Hz, 1.56 Hz), 7.61-7.57 (m, 2H) ,7.33(br,1H),7.28-7.25(m,1H),7.22(s,1H),5.89(br,1H),5.34-5.28(m,1H),4.13-4.09(m,1H),3.27 (s, 3H), 2.27 (s, 3H), 2.15-1.76 (m, 8H), 1.62-1.59 (d, 3H, J = 6.87 Hz).
化合物C28的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.59-8.58(dd,1H,J＝4.06Hz,1.72Hz),8.52-8.50(dd,1H,J＝4.53Hz,0.70Hz),8.08-8.06(d,1H,J＝9.07Hz),7.83-7.80(dd,1H,J＝8.27Hz,1.56Hz),7.61-7.58(d,1H,J＝9.21Hz),7.58-7.57(d,1H,J＝4.53Hz),7.48(br,1H),7.44-7.42(d,1H,J＝8.43Hz)7.29-7.26(m,1H),7.23(s,1H),5.83(br,1H),5.38-5.31(m,1H),4.22-4.15(m,1H),3.22(s,3H),2.27(s,3H),2.35-1.70(m,8H),1.61-1.59(d,3H,J＝7.49Hz).NMR analysis data of compound C28: 1H NMR (400MHz, CDCl3) δ8.59-8.58 (dd, 1H, J = 4.06 Hz, 1.72 Hz), 8.52-8.50 (dd, 1H, J = 4.53 Hz, 0.70 Hz), 8.08-8.06 (d, 1H, J = 9.07 Hz), 7.83-7.80 (dd, 1H, J = 8.27 Hz, 1.56 Hz), 7.61-7.58 (d, 1H, J = 9.21 Hz), 7.58-7.57 (d ,1H,J=4.53Hz),7.48(br,1H),7.44-7.42(d,1H,J=8.43Hz)7.29-7.26(m,1H),7.23(s,1H),5.83(br,1H ), 5.38-5.31 (m, 1H), 4.22-4.15 (m, 1H), 3.22 (s, 3H), 2.27 (s, 3H), 2.35-1.70 (m, 8H), 1.61-1.59 (d, 3H) ,J=7.49Hz).
实施例17Example 17
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000165
Figure PCTCN2020091425-appb-000165
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000166
Figure PCTCN2020091425-appb-000166
1、C29-3的合成1. Synthesis of C29-3
将化合物C29-1(500mg,3.6mmol)和化合物C29-2(420mg,5mmol)溶于DMF(10mL)中，然后加入碳酸钾(1150mg,8.3mmol)，升温至100℃搅拌过夜。待反应结束后冷却至室温，浓缩，加水后乙酸乙酯萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得到565mg化合物C29-3.Compound C29-1 (500 mg, 3.6 mmol) and compound C29-2 (420 mg, 5 mmol) were dissolved in DMF (10 mL), then potassium carbonate (1150 mg, 8.3 mmol) was added, and the temperature was raised to 100° C. and stirred overnight. After the reaction is over, it is cooled to room temperature, concentrated, and water is added and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 565 mg of compound C29-3.
化合物C29-3的核磁分析数据：1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.06-9.05(d,1H,J＝2.03Hz),8.53-8.50(dd,1H,J＝8.59Hz,2.34Hz),7.93-7.91(dd,1H,J＝8.62Hz,0.59Hz),2.66(s,3H),2.41(s,3H).NMR analysis data of compound C29-3: 1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.06-9.05(d,1H,J=2.03Hz),8.53-8.50(dd,1H,J ＝8.59Hz,2.34Hz),7.93-7.91(dd,1H,J＝8.62Hz,0.59Hz), 2.66(s,3H),2.41(s,3H).
2、C29-4的合成2. Synthesis of C29-4
将化合物C29-3(565mg,2.8mmol)和R-叔丁基亚磺酰胺(406mg,3.4mmol)溶于50mL干燥的四氢呋喃中，加入钛酸四乙酯(1275mg,5.6mmol)氮气保护下，升温至80℃搅拌过夜，加入2mL水，过滤，滤饼乙酸乙酯洗涤，滤液浓缩，柱层析纯化得到852mg化合物C29-4.Compound C29-3 (565mg, 2.8mmol) and R-tert-butylsulfinamide (406mg, 3.4mmol) were dissolved in 50mL of dry tetrahydrofuran, and tetraethyl titanate (1275mg, 5.6mmol) was added under nitrogen protection, Warm up to 80°C and stir overnight, add 2mL of water, filter, wash the filter cake with ethyl acetate, concentrate the filtrate, and purify by column chromatography to obtain 852mg of compound C29-4.
化合物C29-4的核磁分析数据：1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.85-8.84(d,1H,J＝2.03Hz),8.27-8.24(dd,1H,J＝8.82Hz,2.67Hz),7.82-7.80(d,1H,J＝4.21Hz),2.74(s,3H),2.43(s,3H),1.27(s,9H).NMR analysis data of compound C29-4: 1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.85-8.84(d,1H,J=2.03Hz), 8.27-8.24(dd,1H,J=8.82 Hz, 2.67 Hz), 7.82-7.80 (d, 1H, J = 4.21 Hz), 2.74 (s, 3H), 2.43 (s, 3H), 1.27 (s, 9H).
3、C29-5的合成3. Synthesis of C29-5
将化合物C29-4(752mg,2.47mmol)溶于干燥的四氢呋喃(8mL)，降温至-78℃，滴加三仲丁基硼氢化锂(7.4ml,7.4mmol，1.0M)，于-78℃下反应1h，-60℃下加甲醇(8mL)淬灭反应，加水稀释，用乙酸乙酯萃取，干燥有机相，减压蒸干，柱层析得产物578mg。Compound C29-4 (752mg, 2.47mmol) was dissolved in dry tetrahydrofuran (8mL), the temperature was reduced to -78°C, and lithium tri-sec-butylborohydride (7.4ml, 7.4mmol, 1.0M) was added dropwise at -78°C After reacting for 1 h, the reaction was quenched by adding methanol (8 mL) at -60°C, diluting with water, extracting with ethyl acetate, drying the organic phase, evaporating to dryness under reduced pressure, and column chromatography to obtain 578 mg of the product.
化合物C29-5的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.33(s,1H),7.79-7.72(m,2H),4.62-4.58(m,1H),2.42(s,3H),1.53-1.51(d,3H,J＝7.77Hz),1.14(s,9H).NMR analysis data of compound C29-5: 1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.33(s,1H),7.79-7.72(m,2H),4.62-4.58(m,1H), 2.42(s,3H), 1.53-1.51(d,3H,J=7.77Hz), 1.14(s,9H).
4、C29-6的合成4. Synthesis of C29-6
将化合物C29-5(200mg,0.65mmol)溶于DCM(1.6mL)和甲醇(0.5mL)中，加入4M盐酸/二氧六环(1.6mL,6.5mmol),室温反应3h，LC-MS检测反应完全，加乙酸乙酯稀释，过滤，乙酸乙酯洗涤滤饼，干燥滤饼得产物129mg。Compound C29-5 (200mg, 0.65mmol) was dissolved in DCM (1.6mL) and methanol (0.5mL), added 4M hydrochloric acid/dioxane (1.6mL, 6.5mmol), reacted at room temperature for 3h, and detected by LC-MS The reaction was complete, diluted with ethyl acetate, filtered, washed the filter cake with ethyl acetate, and dried the filter cake to obtain 129 mg of product.
化合物C29-6的核磁分析数据：1H NMR(400MHz,MeOD-d4)δ10.48(s,1H),8.73(s,1H),8.36-8.33(dd,1H,J＝8.58Hz,2.27Hz),8.06-8.04(d,1H,J＝8.58Hz),4.72-4.68(m,1H),2.63(s,3H),1.71-1.69(d,3H,J＝6.76Hz).NMR analysis data of compound C29-6: 1H NMR (400MHz, MeOD-d4) δ10.48(s,1H),8.73(s,1H),8.36-8.33(dd,1H,J=8.58Hz,2.27Hz) ,8.06-8.04(d,1H,J＝8.58Hz),4.72-4.68(m,1H),2.63(s,3H),1.71-1.69(d,3H,J＝6.76Hz).
5、C29和C30的合成5. Synthesis of C29 and C30
将化合物C29-6(100mg,0.42mmol)和化合物C3-19(162mg,0.42mmol)溶于DMF(3mL)中，加入二异丙基乙胺(0.55ml,3.3mmol)，室温搅拌5min，再加入HATU(238.5mg,0.63mmol)，然后室温搅拌1h。将反应液用乙酸乙酯稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经制备分离得到9mg化合物C29和5mg化合物C30.Dissolve compound C29-6 (100mg, 0.42mmol) and compound C3-19 (162mg, 0.42mmol) in DMF (3mL), add diisopropylethylamine (0.55ml, 3.3mmol), stir at room temperature for 5 min, then HATU (238.5 mg, 0.63 mmol) was added, and then stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, prepared and separated to obtain 9mg compound C29 and 5mg compound C30.
化合物C29的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.61-8.59(dd,1H,J＝4.26Hz,1.72Hz),8.36(br,1H),7.84-7.82(dd,1H,J＝8.88Hz,1.86Hz),7.75-7.73(m,2H),7.31-7.27(m,2H),7.06(br,1H),6.84-6.82(d,1H,J＝8.52Hz),5.83(br,1H),5.17-5.10(m,1H),4.17-4.11(m,1H),3.24(s,3H),2.43(s,3H),2.25(s,3H),2.15-1.79(m,8H),1.52-1.50(d,3H,J＝7.46Hz).NMR analysis data of compound C29: 1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.61-8.59(dd,1H,J=4.26Hz,1.72Hz),8.36(br,1H),7.84-7.82 (dd,1H,J=8.88Hz,1.86Hz),7.75-7.73(m,2H),7.31-7.27(m,2H),7.06(br,1H),6.84-6.82(d,1H,J=8.52 Hz), 5.83 (br, 1H), 5.17-5.10 (m, 1H), 4.17-4.11 (m, 1H), 3.24 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H), 2.15 -1.79(m,8H),1.52-1.50(d,3H,J=7.46Hz).
化合物C30的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.58-8.57(dd,1H,J＝4.26Hz,1.72Hz),8.40-8.39(d,1H,J＝2.13Hz),7.83-7.70(m,3H),7.37(br,1H),7.29-7.26(m,2H),6.74-6.72(d,1H,J＝7.81Hz),5.80(br,1H),5.22-5.14(m,1H),4.20-4.13(m,1H),3.20(s,3H),2.41(s,3H),2.33-2.25(m,2H),2.23(s,3H),2.16-2.13(m,2H),1.95-1.90(m,2H),1.78-1.70(m,2H),1.52-1.50(d,3H,J＝6.75Hz).NMR analysis data of compound C30: 1H NMR(400MHz,CDCl3)δ8.95(s,1H), 8.58-8.57(dd,1H,J=4.26Hz,1.72Hz), 8.40-8.39(d,1H,J= 2.13Hz), 7.83-7.70(m,3H), 7.37(br,1H), 7.29-7.26(m,2H), 6.74-6.72(d,1H,J=7.81Hz), 5.80(br,1H), 5.22-5.14(m,1H), 4.20-4.13(m,1H), 3.20(s,3H), 2.41(s,3H),2.33-2.25(m,2H),2.23(s,3H), 2.16 2.13(m,2H),1.95-1.90(m,2H),1.78-1.70(m,2H),1.52-1.50(d,3H,J=6.75Hz).
实施例18Example 18
本发明合成的化合物：Compounds synthesized by the present invention:
Figure PCTCN2020091425-appb-000167
Figure PCTCN2020091425-appb-000167
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000168
Figure PCTCN2020091425-appb-000168
1、C31-2的合成1. Synthesis of C31-2
将化合物C31-8(2.0g,10mmol)和三甲基硅乙炔(1.7mL,12mmol)溶于干燥的THF(20mL)和三乙胺(20mL)中，然后依次加入CuI(190mg,1mmol)，四三苯基膦钯(580mg，0.5mmol)，升温至30℃搅拌过夜。待反应结束后冷却至室温，减压浓缩，乙酸乙酯稀释。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到2.1g化合物C31-2.Compound C31-8 (2.0g, 10mmol) and trimethylsilylacetylene (1.7mL, 12mmol) were dissolved in dry THF (20mL) and triethylamine (20mL), and then CuI (190mg, 1mmol) was added sequentially, Tetratriphenylphosphine palladium (580mg, 0.5mmol) was heated to 30°C and stirred overnight. After the reaction is over, it is cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 2.1 g of compound C31-2.
化合物C31-2的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.10-9.09(d,1H,J＝1.54Hz),8.19-8.17(dd,1H,J＝8.29Hz,2.14Hz),7.56-7.53(dd,1H,J＝8.12Hz,0.55Hz),2.63(s,3H),0.28(s,9H). NMR analysis data of compound C31-2: 1 H NMR (400MHz, DMSO-d 6 ) δ 9.10-9.09 (d, 1H, J = 1.54 Hz), 8.19-8.17 (dd, 1H, J = 8.29 Hz, 2.14 Hz), 7.56-7.53 (dd, 1H, J = 8.12 Hz, 0.55 Hz), 2.63 (s, 3H), 0.28 (s, 9H).
2、C31-3的合成2. Synthesis of C31-3
将化合物C31-2(1.0g,4.61mmol)溶于20mL无水甲醇中，然后加入无水碳酸钾(1.27g，9.21mmol)，将反应液室温搅拌1h。反应结束后，用乙酸乙酯稀释，然后 过滤出碳酸钾。滤液用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化得605mg化合物C31-3.Compound C31-2 (1.0 g, 4.61 mmol) was dissolved in 20 mL of anhydrous methanol, then anhydrous potassium carbonate (1.27 g, 9.21 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. After the reaction, it was diluted with ethyl acetate, and then potassium carbonate was filtered out. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 605 mg of compound C31-3.
化合物C31-3的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.13(s,1H),8.23-8.20(dd,1H,J＝7.79Hz,1.56Hz),7.60-7.58(d,1H,J＝8.18Hz),3.34(s,1H),2.65(s,3H). NMR analysis data of compound C31-3: 1 H NMR (400MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.23-8.20 (dd, 1H, J = 7.79 Hz, 1.56 Hz), 7.60-7.58 ( d, 1H, J = 8.18 Hz), 3.34 (s, 1H), 2.65 (s, 3H).
3、C31-5的合成3. Synthesis of C31-5
将CuI(63mg，0.33mmol)悬浮于DMF(2mL)和二异丙基乙胺(3mL)的混合溶剂中，依次加入化合物C31-3(237mg,1.64mmol)和化合物C31-4(422mg，3.27mmol)，反应液室温搅拌过夜。反应结束后，用乙酸乙酯稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，经柱层析纯化得到313mg化合物C31-5。CuI (63mg, 0.33mmol) was suspended in a mixed solvent of DMF (2mL) and diisopropylethylamine (3mL), and compound C31-3 (237mg, 1.64mmol) and compound C31-4 (422mg, 3.27) were added sequentially mmol), the reaction solution was stirred at room temperature overnight. After the reaction, it was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 313 mg of compound C31-5.
化合物C31-5的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.11-9.10(d,1H,J＝1.08Hz),8.31-8.25(m,2H),8.08(s,1H),3.99(s,2H),2.64(s,3H),0.18(s,9H). NMR analysis data of compound C31-5: 1 H NMR (400MHz, DMSO-d 6 ) δ9.11-9.10 (d, 1H, J = 1.08 Hz), 8.31-8.25 (m, 2H), 8.08 (s, 1H) ), 3.99(s, 2H), 2.64(s, 3H), 0.18(s, 9H).
4、C31-6的合成4. Synthesis of C31-6
将化合物C31-5(625mg，2.28mmol)溶于四氢呋喃(150ml)中，然后冰水浴冷却下滴加1M四丁基氟化铵的四氢呋喃溶液(2.74ml，2.74mmol)，冰水浴冷却下搅拌1h。反应结束后用饱和食盐水洗涤，乙酸乙酯萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，经柱层析纯化得到363mg化合物C31-6.Compound C31-5 (625mg, 2.28mmol) was dissolved in tetrahydrofuran (150ml), then 1M tetrabutylammonium fluoride solution in tetrahydrofuran (2.74ml, 2.74mmol) was added dropwise under ice-water bath cooling, and stirred under ice-water bath cooling for 1h . After the reaction, it was washed with saturated brine and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 363 mg of compound C31-6.
化合物C31-6的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.13-9.12(d,1H,J＝0.89Hz),8.33-8.27(m,2H),8.21(s,1H),4.20(s,2H),2.66(s,3H). NMR analysis data of compound C31-6: 1 H NMR (400MHz, DMSO-d 6 ) δ9.13-9.12 (d, 1H, J=0.89 Hz), 8.33-8.27 (m, 2H), 8.21 (s, 1H) ), 4.20(s, 2H), 2.66(s, 3H).
5、C31-7的合成5. Synthesis of C31-7
将化合物C31-6(490mg，2.43mmol)和R-叔丁基亚磺酰胺(309mg,3.64mmol)溶于干燥的四氢呋喃(20mL)中，然后加入钛酸四乙酯(2.22g,9.72mmol)，氮气保护下，升温至80℃搅拌过夜。待反应结束后冷却至室温，加入2mL水，减压过滤。滤液用乙酸乙酯萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化，得到575mg化合物C31-7.Compound C31-6 (490mg, 2.43mmol) and R-tert-butylsulfinamide (309mg, 3.64mmol) were dissolved in dry tetrahydrofuran (20mL), and then tetraethyl titanate (2.22g, 9.72mmol) was added Under the protection of nitrogen, the temperature was raised to 80°C and stirred overnight. After the reaction is over, cool to room temperature, add 2 mL of water, and filter under reduced pressure. The filtrate was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 575 mg of compound C31-7.
化合物C31-7的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),8.23-8.22(d,2H,J＝1.47Hz),8.16(s,1H),4.18(s,3H),2.80(s,3H),1.33(s,9H). NMR analysis data of compound C31-7: 1 H NMR (400MHz, DMSO-d 6 ) δ9.06 (s, 1H), 8.23-8.22 (d, 2H, J=1.47 Hz), 8.16 (s, 1H), 4.18(s,3H), 2.80(s,3H), 1.33(s,9H).
6、C31-8的合成6. Synthesis of C31-8
将化合物C31-7(575mg,1.89mmol)溶于干燥的四氢呋喃(30mL)中，氮气保护下，降温至-78℃滴加1M L-selectride四氢呋喃溶液(5.7mL,5.66mmol)，并保持-78℃搅拌1h，TLC检测反应结束后，滴加甲醇淬灭，升至室温，用乙酸乙酯稀释。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到558mg化合物C31-8.Dissolve compound C31-7 (575mg, 1.89mmol) in dry tetrahydrofuran (30mL), under the protection of nitrogen, reduce the temperature to -78℃ and add 1M L-selectride tetrahydrofuran solution (5.7mL, 5.66mmol) dropwise, and keep -78 Stir at °C for 1 h. After the reaction is detected by TLC, it is quenched by adding methanol dropwise, warmed to room temperature, and diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 558 mg of compound C31-8.
化合物C31-8的核磁分析数据： 1H NMR(400MHz,DMSO-d 6)δ8.48(s,1H),8.09-8.04(m,2H),7.69-7.66(dd,1H,J＝8.12Hz,1.48Hz),4.60-4.57(q,1H),4.10(s,3H),1.53(s,3H),1.15(s,9H). NMR analysis data of compound C31-8: 1 H NMR (400MHz, DMSO-d 6 ) δ8.48 (s, 1H), 8.09-8.04 (m, 2H), 7.69-7.66 (dd, 1H, J = 8.12 Hz ,1.48Hz), 4.60-4.57(q,1H), 4.10(s,3H), 1.53(s,3H), 1.15(s,9H).
7、C31-9的合成7. Synthesis of C31-9
将化合物C31-8(498mg,1.62mmol)溶于二氧六环(3mL)和无水甲醇(3mL)的混合溶液中，然后加入的4M盐酸二氧六环溶液(4.1mL)，室温搅拌2h，然后加入甲基叔丁基醚，过滤，干燥得到295mg化合物C31-9.Compound C31-8 (498mg, 1.62mmol) was dissolved in a mixed solution of dioxane (3mL) and anhydrous methanol (3mL), and then 4M hydrochloric acid dioxane solution (4.1mL) was added and stirred at room temperature for 2h , Then added methyl tert-butyl ether, filtered, and dried to obtain 295mg of compound C31-9.
8、C31的合成8. Synthesis of C31
将化合物C31-9(10mg，0.04mmol)和化合物C3-19(16mg，0.04mmol)溶于DMF(0.5ml)中，加入二异丙基乙胺(44mg，0.34mmol)，室温搅拌5min后，再加入HATU(24mg，0.06mmol)，然后室温搅拌1h。将反应液用乙酸乙酯稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经高效液相色谱制备分离得4mg化合物C31。MS[M+H]567.4.Compound C31-9 (10mg, 0.04mmol) and compound C3-19 (16mg, 0.04mmol) were dissolved in DMF (0.5ml), diisopropylethylamine (44mg, 0.34mmol) was added, and after stirring at room temperature for 5 min, Then HATU (24 mg, 0.06 mmol) was added, and then stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and prepared and separated by high performance liquid chromatography to obtain 4 mg of compound C31. MS[M+H]567.4.
对比例1Comparative example 1
Figure PCTCN2020091425-appb-000169
Figure PCTCN2020091425-appb-000169
合成路线及实验过程如下：The synthetic route and experimental process are as follows:
Figure PCTCN2020091425-appb-000170
Figure PCTCN2020091425-appb-000170
1、C32-1和C32-1A的合成1. Synthesis of C32-1 and C32-1A
于250mL单口瓶中加入C1-1(6.92g，40mmol)、对甲氧基苯甲醇(6.07g，44mmol)、THF(100mL)，0℃下分批加入NaH(2.4g，60mmol)，将反应置于室温下反应4h。LC-MS显示反应完毕，搅拌下将反应液倒入水(200mL)中，乙酸乙酯萃取3次，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得10.7g(C32-1和C32-1A的混合物)。C1-1 (6.92g, 40mmol), p-methoxybenzyl alcohol (6.07g, 44mmol), THF (100mL) were added to a 250mL single-necked flask, NaH (2.4g, 60mmol) was added in batches at 0°C, and the reaction Place the reaction at room temperature for 4h. LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (200 mL), extracted with ethyl acetate 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography yielded 10.7 g (C32-1 And C32-1A).
2、C32-2和C32-2A的合成2. Synthesis of C32-2 and C32-2A
于250mL单口瓶中加入C32-1和C32-1A的混合物(8.22g，30mmol)、C1-3(9.77g，33mmol)、Pd(PPh 3) 4(3.47g，3mmol)、K 2CO 3(8.28g，60mmol)、二氧六环/H 2O(120mL/30mL)，N 2保护下将反应置于90℃下反应过夜。LC-MS显示反应完毕，搅拌下将反应液倒入水(300mL)中乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，旋干，柱层析分离，得C32-2A(4.78g)和C32-2(7.54g)。 Add a mixture of C32-1 and C32-1A (8.22g, 30mmol), C1-3 (9.77g, 33mmol), Pd(PPh 3 ) 4 (3.47g, 3mmol), K 2 CO 3 ( 8.28 g, 60 mmol), dioxane/H 2 O (120 mL/30 mL), and the reaction was placed at 90° C. overnight under the protection of N 2 . LC-MS showed that the reaction was complete. Under stirring, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate for 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain C32-2A (4.78). g) and C32-2 (7.54g).
化合物C32-2A的核磁分析数据：1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.6Hz,1H),7.37(d,J＝8.6Hz,2H),6.94–6.86(m,2H),6.67(d,J＝8.6Hz,1H),6.58(d,J＝3.4Hz,1H),5.35(s,2H),3.81(s,6H),3.34(s,3H),2.90–2.56(m,4H),2.28–2.06(m,2H)；NMR analysis data of compound C32-2A: 1H NMR(400MHz,CDCl3)δ7.76(d,J=8.6Hz,1H), 7.37(d,J=8.6Hz,2H), 6.94–6.86(m,2H) ,6.67(d,J=8.6Hz,1H),6.58(d,J=3.4Hz,1H),5.35(s,2H),3.81(s,6H),3.34(s,3H),2.90–2.56( m,4H),2.28–2.06(m,2H);
化合物C32-2的核磁分析数据：1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.9Hz,1H),7.41(d,J＝8.7Hz,2H),7.03(d,J＝7.9Hz,1H),6.94–6.87(m,2H),6.85(dd,J＝4.6,3.3Hz,1H),5.46(s,2H),3.81(d,J＝1.4Hz,6H),3.31(s,3H),2.87–2.75(m,1H),2.67–2.50(m,3H),2.32–2.03(m,2H).。NMR analysis data of compound C32-2: 1H NMR(400MHz,CDCl3)δ7.79(d,J=7.9Hz,1H), 7.41(d,J=8.7Hz,2H), 7.03(d,J=7.9Hz ,1H),6.94–6.87(m,2H),6.85(dd,J=4.6,3.3Hz,1H),5.46(s,2H),3.81(d,J=1.4Hz,6H),3.31(s, 3H), 2.87–2.75(m,1H), 2.67–2.50(m,3H), 2.32–2.03(m,2H).
3、C32-3的合成3. Synthesis of C32-3
于10mL反应器中加入C32-2(1.0g，2.45mmol)、二氯甲烷(6mL)、三氟乙酸(4mL)，室温下反应10h，旋干，加K 2CO 3(aq)，乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，浓缩得粗品(583mg)。 Add C32-2 (1.0g, 2.45mmol), dichloromethane (6mL), trifluoroacetic acid (4mL) into a 10mL reactor, react for 10h at room temperature, spin dry, add K 2 CO 3 (aq), ethyl acetate The ester was extracted 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product (583 mg).
4、C32-4的合成4. Synthesis of C32-4
于10mL反应器中加入C32-3(703mg，2.4mmol)、甲苯(5mL)、POCl 3(10mL)，110℃下反应10h，浓缩，加饱和K 2CO 3水溶液，乙酸乙酯萃取3次，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩得粗品(430mg)。 Add C32-3 (703mg, 2.4mmol), toluene (5mL), POCl 3 (10mL) into a 10mL reactor, react for 10h at 110°C, concentrate, add saturated K 2 CO 3 aqueous solution, and extract 3 times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (430 mg).
5、C32-5的合成5. Synthesis of C32-5
于100mL单口瓶中加入C32-4(320mg，1.05mmol)、C1-17(227mg，1.15mmol)、Pd 2(dba) 3(92mg,0.1mmol)、t-BuXPhos(89mg,0.21mmol)、KOAc(206mg,2.1mmol)、dioxane(10mL)，N 2氛围下将反应置于90℃下反应过夜。LC-MS显示反应完毕，减压浓缩，残留物加入乙酸乙酯，食盐水洗涤有机相，有机相干燥浓缩得粗品。粗品经柱层析得290mg产品。 Add C32-4 (320mg, 1.05mmol), C1-17 (227mg, 1.15mmol), Pd 2 (dba) 3 (92mg, 0.1mmol), t-BuXPhos (89mg, 0.21mmol), KOAc into a 100mL single-mouth bottle (206mg, 2.1mmol), dioxane (10mL), the reaction was placed at 90°C overnight under N 2 atmosphere. LC-MS showed that the reaction was complete, it was concentrated under reduced pressure, the residue was added with ethyl acetate, the organic phase was washed with brine, and the organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography to obtain 290 mg of product.
6、C32-6的合成6. Synthesis of C32-6
于50mL单口瓶中加入C32-5(1.81g，3.86mmol)、LiOH·H 2O(648mg，15.44mmol)、THF/MeOH/H 2O(10mL/10mL/5mL)，将反应置于50℃下反应2h。LC-MS显示反应完毕，减压浓缩得粗品1.58g。 Add C32-5 (1.81g, 3.86mmol), LiOH·H 2 O (648mg, 15.44mmol), THF/MeOH/H 2 O (10mL/10mL/5mL) into a 50mL single-mouth flask, and place the reaction at 50°C Reaction for 2h. LC-MS showed that the reaction was complete, and concentrated under reduced pressure to obtain 1.58 g of crude product.
7、C32的合成7. Synthesis of C32
于50mL单口瓶中加入C32-6(108mg，0.3mmol)、C1-7(92mg，0.33mmol)，DMF(7mL)、二异丙基乙胺(310mg，2.4mmol)，室温搅拌5min，加入HATU(134mg，0.35mmol)，室温下反应30min。LC-MS显示反应完毕，将反应液倒入水(20mL)中乙酸乙酯萃取3次，饱和食盐水洗，无水硫酸钠干燥，旋干，柱层析得粗品后制备分离得C32(123mg，purity:95.7％)，[M+H]:542.3。Add C32-6 (108mg, 0.3mmol), C1-7 (92mg, 0.33mmol), DMF (7mL), and diisopropylethylamine (310mg, 2.4mmol) into a 50mL single-mouth flask, stir at room temperature for 5min, and add HATU (134mg, 0.35mmol), react for 30min at room temperature. LC-MS showed that the reaction was complete. The reaction solution was poured into water (20mL) and extracted with ethyl acetate for 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, column chromatography to obtain the crude product and then prepared and separated to obtain C32 (123mg, purity: 95.7%), [M+H]: 542.3.
化合物C32的核磁分析数据：1H NMR(400MHz,CDCl3)δ8.47(t,J＝8.3Hz,1H),8.38(d,J＝4.6Hz,2H),7.92(d,J＝8.5Hz,1H),7.78(dd,J＝8.5,2.1Hz,1H),7.59(d,J＝4.3Hz,1H),7.25–7.15(m,1H),6.91(dd,J＝7.9,5.2Hz,1H),6.73(d,J＝8.6Hz,1H),5.86(d,J＝4.3Hz,1H),5.19(dd,J＝9.8,4.8Hz,1H),3.26(d,J＝5.7Hz,3H),3.08–2.44 (m,4H),2.40(d,J＝2.1Hz,3H),2.19–2.01(m,2H),1.60(d,J＝7.0Hz,3H).NMR analysis data of compound C32: 1H NMR(400MHz,CDCl3)δ8.47(t,J=8.3Hz,1H), 8.38(d,J=4.6Hz,2H),7.92(d,J=8.5Hz,1H ), 7.78(dd,J=8.5,2.1Hz,1H),7.59(d,J=4.3Hz,1H),7.25-7.15(m,1H),6.91(dd,J=7.9,5.2Hz,1H) , 6.73(d,J=8.6Hz,1H), 5.86(d,J=4.3Hz,1H), 5.19(dd,J=9.8,4.8Hz,1H), 3.26(d,J=5.7Hz,3H) ,3.08–2.44 (m,4H), 2.40(d,J=2.1Hz,3H), 2.19–2.01(m,2H), 1.60(d,J=7.0Hz,3H).
试验例1酶活性试验Test Example 1 Enzyme Activity Test
下面上述实施例部分化合物及对比例进行生物活性测试实验。The biological activity test experiments of some of the compounds in the above examples and comparative examples are carried out below.
生物活性测试实验过程如下：The biological activity test experiment process is as follows:
使用Kinase activity Assay方法在ATP Km浓度下筛选实施例制备的化合物对野生型RET激酶的活性，并使用星形孢菌素(Staurosporine)做对照品，化合物的生物活性筛选将在10个浓度下重复测定。Use the Kinase activity Assay method to screen the activity of the compounds prepared in the example against wild-type RET kinase at the concentration of ATP Km, and use Staurosporine as the reference substance. The biological activity screening of the compounds will be repeated at 10 concentrations Determination.
1、受试样品1. Test sample
各样品分别配成浓度为10mM的溶液。Each sample was prepared into a solution with a concentration of 10 mM.
2、实验方法2. Experimental method
一、为实验用激酶准备基本缓冲溶液和淬灭缓冲溶液1. Prepare basic buffer solution and quenching buffer solution for experimental kinase
20mM Hepes(pH 7.5)、10mM MgCl 2、1mM EGTA、0.02％Brij35、0.02mg/ml BSA、0.1mM Na 3VO 4、2mM DTT、1％DMSO。 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35, 0.02mg/ml BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO.
二、为实验用激酶准备化合物2. Prepare compounds for experimental kinases
测试化合物在100％二甲基亚砜中溶解至特定浓度。用Integra Viaflo Assist辅助DMSO进行(连续)稀释。The test compound is dissolved to a specific concentration in 100% dimethyl sulfoxide. Use Integra Viaflo Assist to assist DMSO for (serial) dilution.
三、反应步骤Three, reaction steps
将激酶加入新制备的基本反应缓冲液Add kinase to newly prepared basic reaction buffer
向上述底物溶液中加入任何所需的辅因子。Add any required cofactors to the above substrate solution.
将野生型RET激酶加入到底物溶液中，轻轻混合；Add wild-type RET kinase to the substrate solution and mix gently;
用Acoustic technology(Echo550；nanoliter range)将100％二甲基亚砜中的化合物送入激酶反应混合物中，在室温下培养20分钟。Use Acoustic technology (Echo550; nanoliter range) to transfer the compound in 100% dimethyl sulfoxide to the kinase reaction mixture and incubate at room temperature for 20 minutes.
向反应混合物中加入33P-ATP(Specific activity 10Ci/l)，开始反应。Add 33P-ATP (Specific activity 10Ci/l) to the reaction mixture to start the reaction.
室温下孵育2小时Incubate at room temperature for 2 hours
用filter-binding方法检测放射性。Use filter-binding method to detect radioactivity.
激酶活性数据表示为与媒剂(二甲基亚砜)反应相比，试验样品中剩余激酶活性的百分比。使用Prism(GRAPHPAD软件)获得IC50值和曲线拟合。The kinase activity data is expressed as the percentage of kinase activity remaining in the test sample compared to the vehicle (dimethyl sulfoxide) reaction. Prism (GRAPHPAD software) was used to obtain IC50 values and curve fitting.
得到的受试样品对野生型RET的抑制活性IC50(nM)值如表1所示。Table 1 shows the IC50 (nM) value of the obtained test sample's inhibitory activity against wild-type RET.
表1Table 1
Figure PCTCN2020091425-appb-000171
Figure PCTCN2020091425-appb-000171
Figure PCTCN2020091425-appb-000172
Figure PCTCN2020091425-appb-000172
从上表可知，通过体外生物活性筛选，以星形孢菌素(Staurosporine)为对照品，本申请所合成的化合物对野生型RET激酶均有很好的抑制能力，有望进一步开发成为用于调节RET激酶活性或治疗RET相关疾病方面的药物。并且从C7和对比例C32的活性数据可以看出，氰基的位置对于化合物对野生型RET的抑制活性的影响很大。It can be seen from the above table that through in vitro biological activity screening and using Staurosporine as a reference substance, the compound synthesized in this application has a good inhibitory ability on wild-type RET kinase, and is expected to be further developed as a regulator for regulation RET kinase activity or drugs for the treatment of RET-related diseases. And from the activity data of C7 and Comparative Example C32, it can be seen that the position of the cyano group has a great influence on the compound's inhibitory activity on wild-type RET.
试验例2细胞抗增殖实验Test Example 2 Cell anti-proliferation experiment
一、实验材料1. Experimental materials
RPMI-1640购自BI。RPMI-1640 was purchased from BI.
Fetal bovine serum购自BI。Fetal bovine serum was purchased from BI.
Figure PCTCN2020091425-appb-000173
购自Promega。
Figure PCTCN2020091425-appb-000173
Purchased from Promega.
Dimethyl sulfoxide(DMSO)购自TCI。Dimethyl sulfoxide (DMSO) was purchased from TCI.
BaF3细胞购自RIKEN BRC CELL BANK。BaF3 cells were purchased from RIKEN BRC CELL BANK.
Ba/F3-KIF5B-RET、Ba/F3-KIF5B-RET-V804L和Ba/F3-KIF5B-RET-V804M细胞由合肥中科普瑞昇生物医药科技有限公司构建。Ba/F3-KIF5B-RET, Ba/F3-KIF5B-RET-V804L and Ba/F3-KIF5B-RET-V804M cells were constructed by Hefei Zhongke Puruisheng Biomedical Technology Co., Ltd.
Ba/F3-KIF5B-RET、Ba/F3-KIF5B-RET-V804L和Ba/F3-KIF5B-RET-V804M培养基：RPMI-1640+10％FBS+1％P/S。Ba/F3-KIF5B-RET, Ba/F3-KIF5B-RET-V804L and Ba/F3-KIF5B-RET-V804M medium: RPMI-1640+10%FBS+1%P/S.
读板仪器:Molecular DevicesPlate reader: Molecular Devices
二、实验方法2. Experimental method
1、化合物的稀释1. Dilution of compounds
用DMSO配制1000x化合物溶液，用生长培养基稀释化合物至20倍终浓度，添加2μl 1000x cpd 98μl生长介质。Prepare 1000x compound solution with DMSO, dilute the compound to 20 times the final concentration with growth medium, and add 2μl 1000x cpd 98μl growth medium.
2、细胞接种2. Cell seeding
将悬浮细胞向下旋转，在生长培养基中复苏，然后用细胞计数器计数。将细胞悬液在生长培养基中稀释至所需浓度。95μL的细胞悬浊液被送往96孔板。加入5μL20X化合物到95孔板，最终每孔DMSO浓度为0.1％；在37℃，5％CO2孵育72hSpin down the suspended cells, resuscitate them in growth medium, and count them with a cell counter. The cell suspension is diluted to the desired concentration in growth medium. 95 μL of cell suspension was sent to a 96-well plate. Add 5μL of 20X compound to a 95-well plate, and the final DMSO concentration per well is 0.1%; incubate at 37℃, 5% CO2 for 72h
3、测量3. Measurement
在测量前将测定板平衡到室温，每孔加入50μl
Figure PCTCN2020091425-appb-000174
试剂，在摇床上混合2分钟，室温孵育10分钟，用Paradigm记录。 Before measurement, equilibrate the assay plate to room temperature, add 50μl to each well
Figure PCTCN2020091425-appb-000174
The reagents were mixed on a shaker for 2 minutes, incubated at room temperature for 10 minutes, and recorded with Paradigm.
三、数据分析Three, data analysis
细胞活性根据公式Cell viability(CV％)＝(RLU compound-RLU blank)/(RLU control-RLU blank)*100％，用Graphpad 7.0软件进行分析，计算出相应的IC50数据，如表2所示Cell viability(CV%)=(RLU compound-RLU blank)/(RLU control-RLU blank)*100%, analyze with Graphpad 7.0 software, calculate the corresponding IC50 data, as shown in Table 2.
表2Table 2
Figure PCTCN2020091425-appb-000175
Figure PCTCN2020091425-appb-000175
由表2可以看出，本发明化合物对Ba/F3(WT-RET、RET-V804L和RET-V804M)有较好抑制效果，尤其是化合物C15和C26。It can be seen from Table 2 that the compounds of the present invention have a good inhibitory effect on Ba/F3 (WT-RET, RET-V804L and RET-V804M), especially compounds C15 and C26.
试验例3药物代谢试验Test Example 3 Drug Metabolism Test
将SD大鼠分别单次静脉和灌胃给予BLU-667、化合物C2、化合物C4和化合物C8四个小分子化合物，于不同时间点采集血样，测定给予受试物后大鼠血浆中药物浓度并计算相关药代参数。SD rats were given four small molecule compounds BLU-667, compound C2, compound C4 and compound C8 once intravenously and intragastrically, respectively. Blood samples were collected at different time points to determine the concentration of the drug in the rat plasma after administration of the test substance. Calculate relevant pharmacokinetic parameters.
1、受试样品溶液制备1. Preparation of test sample solution
供试品给药溶液的配制在苏州大学药学院完成。配制方法如下：The preparation of the test substance administration solution was completed in the School of Pharmacy of Soochow University. The preparation method is as follows:
代号为BLU-667、C2、C4、C8的化合物溶媒是10％NMP+49％PEG400+1％Tween80+40％Water。具体配制方法为：分别称取适量受试物，分别溶于10％NMP+49％PEG400+1％Tween80+40％Water中，涡旋混匀，备用。The compound solvent code-named BLU-667, C2, C4, C8 is 10% NMP+49%PEG400+1%Tween80+40%Water. The specific preparation method is as follows: Weigh an appropriate amount of the test substance and dissolve it in 10% NMP + 49% PEG400 + 1% Tween 80 + 40% Water, vortex and mix well, and set aside.
2、供试品溶液分析2. Analysis of test solution
配制的供试品溶液由本实验机构分析部门采用LC-MS/MS进行检测分析.The prepared test solution is tested and analyzed by the analysis department of this experimental institution using LC-MS/MS.
3、动物接收与适应3. Animal reception and adaptation
健康雄性SD大鼠用于该研究；动物体重：150-200g。所有动物给药前禁食，给药后4小时恢复给食。Healthy male SD rats were used in the study; animal weight: 150-200 g. All animals were fasted before administration and resumed feeding 4 hours after administration.
4、动物给药4. Animal administration
给药信息如表3所示Dosing information is shown in Table 3
表3table 3
Figure PCTCN2020091425-appb-000176
Figure PCTCN2020091425-appb-000176
5、样品采集与处理5. Sample collection and processing
采血时间点为：The blood sampling time points are:
静脉给药(1、3、5组)：给药后0.0833，0.25，0.5，1，2，4，8，12和24h。(≤2hr的时间点±2min，其余各点±15min。)Intravenous administration (group 1, 3, 5): 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12 and 24h after administration. (≤2hr time point ±2min, other points ±15min.)
口服给药：(2、4、6、7组)：给药后0.25，0.5，1，2，4，8，12和24h。(≤2hr的时间点±2min，其余各点±15min。)Oral administration: (groups 2, 4, 6, 7): 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h after administration. (≤2hr time point ±2min, other points ±15min.)
每只动物每次经颈静脉采集血液约0.1mL，以EDTA或肝素钠作为抗凝剂。血液样本采集后置于冰上，离心分离血浆(离心条件：5000转/分钟，6分钟，4℃)。Each animal collects about 0.1 mL of blood through the jugular vein each time, and uses EDTA or heparin sodium as an anticoagulant. The blood samples were collected on ice and centrifuged to separate the plasma (centrifugation conditions: 5000 rpm, 6 minutes, 4°C).
大鼠血浆样品由实验机构分析部门采用LC-MS/MS进行分析。Rat plasma samples were analyzed by LC-MS/MS by the analysis department of the experimental institution.
6、药物代谢动力学分析6. Pharmacokinetic analysis
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin非房室模型分别计算供试品的药代动力学参数AUC 0→t、AUC 0→∞、MRT 0→∞、C max、T max、Vss、F、CL和T 1/2及其平均值和标准差。 According to the blood concentration data of the drug, the pharmacokinetic calculation software WinNonlin non-compartmental model was used to calculate the pharmacokinetic parameters of the test product AUC 0→t , AUC 0→∞ , MRT 0→∞ , C max , T max , Vss, F, CL and T 1/2 and their mean and standard deviation.
7、实验结果7. Experimental results
SD大鼠静脉注射和单次灌胃口服BLU-667、化合物C2、化合物C4和化合物C8后血浆中的BLU-667、化合物C2、化合物C4和化合物C8的主要药代动力学参数如表3所示The main pharmacokinetic parameters of BLU-667, compound C2, compound C4 and compound C8 in plasma after intravenous injection and single oral gavage of BLU-667, compound C2, compound C4 and compound C8 in SD rats are shown in Table 3. Show
表3table 3
Figure PCTCN2020091425-appb-000177
Figure PCTCN2020091425-appb-000177
从表3可以看出，本申请化合物具有较好的药物代谢，尤其是化合物C4，其最大血药浓度(Cmax)和血浆暴露量AUC相对于对照化合物分别增加3～4倍和2～3倍，因此，本发明化合物具有更好的生物利用度，有望进一步开发成为用于调节RET激酶活性或治疗RET相关疾病方面的药物。It can be seen from Table 3 that the compound of the present application has better drug metabolism, especially compound C4. Its maximum blood concentration (Cmax) and plasma exposure AUC are respectively increased by 3 to 4 times and 2 to 3 times compared with the control compound. Therefore, the compounds of the present invention have better bioavailability and are expected to be further developed as drugs for regulating RET kinase activity or treating RET-related diseases.
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效变换，或直接或间接运用在其他相关的技术领域，均包括在本发明的专利保护范围内。The above are only the embodiments of the present invention and do not limit the patent scope of the present invention. Any equivalent transformation made by using the content of the present invention, or directly or indirectly applied to other related technical fields, are included in the present invention. Within the scope of patent protection.

Claims (14)

  1. 一种用作RET激酶抑制剂的化合物，所述化合物为式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，A compound used as a RET kinase inhibitor, said compound being a compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
    Figure PCTCN2020091425-appb-100001
    Figure PCTCN2020091425-appb-100001
    其中：among them:
    R 1为取代或未取代的5-6元杂环基或5-6元杂芳基；所述取代是指任选地被一个或多个R 2取代； R 1 is a substituted or unsubstituted 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the substitution refers to optionally substituted by one or more R 2 ;
    X 3选自：O、NR 8、CR 9R 10、
    Figure PCTCN2020091425-appb-100002
    其中，R 8和R 11各自独立地选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6卤代烷基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳烷基、C3～C6杂环烷基；R 9和R 10各自独立地选自：氢、卤素、C1～C6烷基、C1～C6卤代烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基；     X 3 is selected from: O, NR 8 , CR 9 R 10 ,
    Figure PCTCN2020091425-appb-100002
    Wherein, R 8 and R 11 are each independently selected from: hydrogen, C1～C6 alkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 haloalkyl, C1～C6 heteroalkyl, C3～C6 ring Alkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, aralkyl, C3-C6 heterocycloalkyl; R 9 and R 10 are each independently selected from: hydrogen, halogen, C1-C6 alkane Group, C1～C6 haloalkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C3～C6 cycloalkyl, C3～C6 halocycloalkyl, Aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
    W环为取代或未取代的亚杂环基或亚杂芳基，所述取代是指任选地被0-2个R 5取代； Ring W is a substituted or unsubstituted heterocyclylene or heteroarylene, and the substitution means optionally substituted with 0-2 R 5 ;
    环Q1任选自：3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；环Q1上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；Ring Q1 is optionally selected from: 3 to 7-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged rings, and may contain 0 to 3 heteroatoms, and heteroatoms are optionally selected from N, O, S; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～ C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl;
    X 5选自：C(O)、S(O)、S(O) 2、
    Figure PCTCN2020091425-appb-100003
    X 5 is selected from: C(O), S(O), S(O) 2 ,
    Figure PCTCN2020091425-appb-100003
    X 6选自：CR 9、N、O； X 6 is selected from: CR 9 , N, O;
    R 2任选自：氢、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、烷胺基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from: hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C1～C6 alkylamino, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy Group, alkylamino group, cycloalkyl group and heteroalkyl group are optionally and independently substituted with 0-5 Ra ;
    A任选自：3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；A环上的任意氢原子可被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；A is optionally selected from: 3 to 7-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged rings, and may contain 0 to 3 heteroatoms, and heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on the A ring can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 Thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl;
    R 3任选自：氢、氘、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、烷胺基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 3 is optionally selected from: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each alkyl group, Alkoxy, alkylamino, cycloalkyl and heteroalkyl are optionally and independently substituted with 0-5 Ra ;
    R 4各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代； R 4 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ) , -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C (O)OR 7 , -(C1～C6 alkylene) -N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 ) (R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0 to 5 R a;
    R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氧代基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代； R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, oxo, cyano, -C(O)R 6 , -OC (O)R 6 , -C(O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 ) (R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P( O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, Aralkyl, heterocyclyl and heterocycloalkyl are each independently substituted with 0-5 Ra ;
    R 6和R 7各自独立地选自：H、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； R 6 and R 7 are each independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkane Group, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
    R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基； R a optionally from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy group, C1 ~ C6 alkyl group, a cycloalkyl group, a heterocyclic group, or a cyano group;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    n为0或1；n is 0 or 1;
    限定条件是：当环W为取代或未取代的6元杂芳基时，环W被X 4取代，其中，X 4选自：CN、
    Figure PCTCN2020091425-appb-100004
    The limiting condition is: when ring W is a substituted or unsubstituted 6-membered heteroaryl group, ring W is substituted by X 4 , wherein X 4 is selected from: CN,
    Figure PCTCN2020091425-appb-100004
    且Q1仅通过Q1环上的碳原子与环W相连。And Q1 is only connected to ring W through a carbon atom on the Q1 ring.
  2. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂 化物或前药，其具有式(Ⅱ)、式(Ⅲ)或式(Ⅳ)所示的结构，The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which has the formula (II), formula (III) or formula (IV) Structure,
    Figure PCTCN2020091425-appb-100005
    Figure PCTCN2020091425-appb-100005
    其中：among them:
    A任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；A is optionally selected from a saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring of 3 to 7 members, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S;
    环Q1任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；环Q1上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；在式(Ⅱ)中，Q1仅通过Q1环上的碳原子与环B相连；Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 Thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl; in the formula In (II), Q1 is connected to ring B only through the carbon atom on ring Q1;
    R 1任选自以下结构中的一种： R 1 is optionally selected from one of the following structures:
    Figure PCTCN2020091425-appb-100006
    Figure PCTCN2020091425-appb-100006
    R 2任选自氢、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl The group is optionally and independently substituted with 0-5 Ra ;
    R 3任选自氢、氘、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 3 is optionally selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each of alkyl, alkoxy, cycloalkyl and Heteroalkyl is optionally and independently substituted with 0-5 Ra ;
    R a任选自C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、环烷基、杂环烷基或氰基； R a is optionally selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano;
    X 1、X 2各自独立地选自N或CR 5； X 1 and X 2 are each independently selected from N or CR 5 ;
    X 3选自O、NR 8、CR 9R 10、
    Figure PCTCN2020091425-appb-100007
    其中R 8和R 11各自独立地选自氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6卤代烷基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳烷基、C3～C6杂环烷基；R 9和R 10各自独立地选自氢、卤素、C1～C6烷基、C1～C6卤代烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、C3～C6卤代环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基；     X 3 is selected from O, NR 8 , CR 9 R 10 ,
    Figure PCTCN2020091425-appb-100007
    Wherein R 8 and R 11 are each independently selected from hydrogen, C1～C6 alkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 haloalkyl, C1～C6 heteroalkyl, C3～C6 cycloalkyl , C3-C6 halocycloalkyl, aryl, heteroaryl, aralkyl, C3-C6 heterocycloalkyl; R 9 and R 10 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1 ～C6 haloalkyl, C2～C6 alkenyl, C2～C6 alkynyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C3～C6 cycloalkyl, C3～C6 halocycloalkyl, aryl, Heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
    X 4选自CN、
    Figure PCTCN2020091425-appb-100008
    X 4 is selected from CN,
    Figure PCTCN2020091425-appb-100008
    X 5选自C(O)、S(O)、S(O) 2、
    Figure PCTCN2020091425-appb-100009
    X 5 is selected from C(O), S(O), S(O) 2 ,
    Figure PCTCN2020091425-appb-100009
    X 6选自CR 9、N、O； X 6 is selected from CR 9 , N, O;
    R 4、R 5各自独立地任选自氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R 6和R 7各自独立地选自C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 heteroalkyl, cycloalkyl , Aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C( O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl is each Independently substituted by 0-5 Ra ; R 6 and R 7 are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hetero Alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
    环Q2任选自五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；Ring Q2 is optionally selected from a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N , O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl , C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl base;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    n为0或1。n is 0 or 1.
  3. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(2)、式(3)或式(4)所示的结构，The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which has the formula (2), formula (3) or formula (4) Structure,
    Figure PCTCN2020091425-appb-100010
    Figure PCTCN2020091425-appb-100010
    Figure PCTCN2020091425-appb-100011
    Figure PCTCN2020091425-appb-100011
    其中：among them:
    A任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；A is optionally selected from a saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring of 3 to 7 members, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S;
    环Q1任选自3～7元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S；环Q1上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；在式(2)中，Q1仅通过Q1环上的碳原子与环B相连；Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N, O, S ; Any hydrogen atom on ring Q1 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1～C6 alkyl, C1～C6 haloalkyl, C1～C6 Thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl; in the formula In (2), Q1 is connected to ring B only through the carbon atom on ring Q1;
    R 1任选自以下结构中的一种： R 1 is optionally selected from one of the following structures:
    Figure PCTCN2020091425-appb-100012
    Figure PCTCN2020091425-appb-100012
    Figure PCTCN2020091425-appb-100013
    Figure PCTCN2020091425-appb-100013
    R 2任选自氢、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 2 is optionally selected from hydrogen, C1～C6 alkyl, C1～C6 alkoxy, C3～C6 cycloalkyl, C1～C6 heteroalkyl, each of which is alkyl, alkoxy, cycloalkyl and heteroalkyl The group is optionally and independently substituted with 0-5 Ra ;
    R 3任选自氢、氘、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基、C1～C6杂烷基，其中每个烷基、烷氧基、环烷基和杂烷基任选且独立地被0～5个R a取代； R 3 is optionally selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, wherein each of alkyl, alkoxy, cycloalkyl and Heteroalkyl is optionally and independently substituted with 0-5 Ra ;
    R a任选自C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、环烷基、杂环烷基或氰基； R a is optionally selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocycloalkyl or cyano;
    X 1、X 2各自独立地选自N或CR 5； X 1 and X 2 are each independently selected from N or CR 5 ;
    R 4、R 5各自独立地任选自氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、卤素、C1～C6杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基、杂环烷基、硝基、氰基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1～C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1～C6亚烷基)-S(O) 2R 6、-(C1～C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1～C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中每个烷基、烯基、炔基、烷氧基、杂烷基、环烷基、芳基、杂芳基、芳氧基、芳烷基、杂环基和杂环烷基各自独立地被0～5个R a取代；R 6和R 7各自独立地选自C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6杂烷基、C3～C6环烷基、芳基、杂芳基、芳氧基、芳烷基、C3～C6杂环烷基、C1～C6烷胺基、C3～C6环烷胺基； R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 heteroalkyl, cycloalkyl , Aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocycloalkyl, nitro, cyano, -C(O)R 6 , -OC(O)R 6 , -C( O)OR 6 , -(C1～C6 alkylene) -C(O)R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1～C6 alkylene)-S(O) 2 R 6 , -(C1～C6 alkylene)-S(O) 2 -N(R 6 )(R 7 ), -N(R 6 )(R 7 ), -C(O)-N(R 6 )(R 7 ), -N(R 6 )-C(O)R 7 , -N(R 6 )-C(O)OR 7 , -(C1～C6 alkylene)-N(R 6 )-C(O)R 7 , -N(R 6 )S(O) 2 R 7 and -P(O)(R 6 )(R 7 ); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl is each Independently substituted by 0-5 Ra ; R 6 and R 7 are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hetero Alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino;
    环Q2任选自五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基；Ring Q2 is optionally selected from a five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, and the heteroatoms are optionally selected from N , O, S, any hydrogen atoms on ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl , C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl or heteroaryl base;
    m为0、1、2、3、4、5或6。m is 0, 1, 2, 3, 4, 5 or 6.
  4. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂 化物或前药，W环选自下组：
    Figure PCTCN2020091425-appb-100014
    Figure PCTCN2020091425-appb-100015
    The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the W ring is selected from the following group:
    Figure PCTCN2020091425-appb-100014
    Figure PCTCN2020091425-appb-100015
    其中，
    Figure PCTCN2020091425-appb-100016
    为单键或双键；     among them,
    Figure PCTCN2020091425-appb-100016
    Single bond or double bond;
    R 12独立地选自：H、卤素、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、硝基、氰基、氨基； R 12 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, amino;
    各Y 1、Y 2、Y 3独立地选自：N、O、CR 13、NR 17、CR 13R 14； Each Y 1 , Y 2 , and Y 3 is independently selected from: N, O, CR 13 , NR 17 , CR 13 R 14 ;
    R 13、R 14、R 15、R 16各自独立地选自：H、卤素、C1～C6烷基、C1～C6烷氧基、C1～C6烷胺基、硝基、氰基、氨基；或者R 13和R 14与其连接的C原子一起形成羰基 (C＝O)；或者R 15和R 16与其连接的C原子一起形成羰基(C＝O)； R 13 , R 14 , R 15 , and R 16 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, amino; or R 13 and R 14 together with the C atom to which they are connected form a carbonyl group (C=O); or R 15 and R 16 together with the C atom to which they are connected form a carbonyl group (C=O);
    R 17选自：H、C1～C6烷基。 R 17 is selected from: H, C1-C6 alkyl.
  5. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式2'所示的结构The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which has the structure shown in formula 2'
    Figure PCTCN2020091425-appb-100017
    Figure PCTCN2020091425-appb-100017
    其中，
    Figure PCTCN2020091425-appb-100018
    为单键或双键；     among them,
    Figure PCTCN2020091425-appb-100018
    Single bond or double bond;
    各R 17独立地选自：氘、卤素、羟基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基； Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
    f为0、1、2、3、4、5、6、7、8或9；f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
    R 1、R 2、R 3、R 4、A和m的定义如权利要求1所述；X 1、X 2的定义如权利要求2所述。 The definitions of R 1 , R 2 , R 3 , R 4 , A and m are as described in claim 1; the definitions of X 1 and X 2 are as described in claim 2.
  6. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式3'所示的结构The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which has the structure represented by formula 3'
    Figure PCTCN2020091425-appb-100019
    Figure PCTCN2020091425-appb-100019
    其中，
    Figure PCTCN2020091425-appb-100020
    为单键或双键；     among them,
    Figure PCTCN2020091425-appb-100020
    Single bond or double bond;
    Figure PCTCN2020091425-appb-100021
    为单键时，Y 4选自：N或CR 17，
    Figure PCTCN2020091425-appb-100021
    When it is a single bond, Y 4 is selected from: N or CR 17 ,
    Figure PCTCN2020091425-appb-100022
    为双键时，Y 4为C；
    Figure PCTCN2020091425-appb-100022
    When it is a double bond, Y 4 is C;
    各R 17独立地选自：氘、卤素、羟基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基； Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
    f为0、1、2、3、4、5、6、7、8或9；f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
    p为0、1、2、3；p is 0, 1, 2, 3;
    R 1、R 2、R 3、R 4、A和m的定义如权利要求1所述；X 2、Q2的定义如权利要求2所述。 The definitions of R 1 , R 2 , R 3 , R 4 , A and m are as set forth in claim 1; the definitions of X 2 and Q2 are as set forth in claim 2.
  7. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式4'所示的结构The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which has the structure represented by formula 4'
    Figure PCTCN2020091425-appb-100023
    Figure PCTCN2020091425-appb-100023
    其中，
    Figure PCTCN2020091425-appb-100024
    为单键或双键；     among them,
    Figure PCTCN2020091425-appb-100024
    Single bond or double bond;
    Figure PCTCN2020091425-appb-100025
    为单键时，Y 4选自：N或CR 17；
    Figure PCTCN2020091425-appb-100025
    When it is a single bond, Y 4 is selected from: N or CR 17 ;
    Figure PCTCN2020091425-appb-100026
    为双键时，Y 4为C；
    Figure PCTCN2020091425-appb-100026
    When it is a double bond, Y 4 is C;
    各R 17独立地选自：氘、卤素、羟基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6烷胺基、C3～C6环烷基； Each R 17 is independently selected from: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl;
    f为0、1、2、3、4、5、6、7、8或9；f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
    p为0、1、2、3；p is 0, 1, 2, 3;
    R 1、R 2、R 3、R 4、A和m的定义如权利要求1所述；X 2、Q2的定义如权利要求2所述。 The definitions of R 1 , R 2 , R 3 , R 4 , A and m are as set forth in claim 1; the definitions of X 2 and Q2 are as set forth in claim 2.
  8. 如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，其具有式5'或者6'所示的结构The compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, characterized in that it has a structure represented by formula 5'or 6'
    Figure PCTCN2020091425-appb-100027
    Figure PCTCN2020091425-appb-100027
    其中，X 2、X 7、X 8、X 9、X 10各自独立地选自：N或CR 5，且X 7、X 8至少有一个为N； Wherein, X 2 , X 7 , X 8 , X 9 , and X 10 are each independently selected from: N or CR 5 , and at least one of X 7 and X 8 is N;
    R 5各自独立地任选自：氢、C1～C6烷基、C2～C6烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷胺基、卤素、C1～C6杂烷基、环烷基、硝基、氰基、氨基；其中每个烷基、烯基、炔基、烷氧基、烷胺基、杂烷基、环烷基各自独立地被0～5个R a取 代；R a任选自：C1～C6烷基、卤素、羟基、C1～C6杂烷基、C1～C6烷氧基、C1～C6烷胺基、环烷基、杂环烷基或氰基；环Q2任选自：五元、六元或七元的饱和环、不饱和环、芳香环、杂芳环、螺环或桥环，且可以含有0～3个杂原子，杂原子任选自N、O、S，环Q2上的任意氢原子可以被以下取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、酮羰基、氨基、C1～C6烷基、C1～C6卤代烷基、C1～C6硫代烷基、C1～C6烷氧基、C1～C6杂烷基、C1～C6烷胺基、C3～C6环烷基、C3～C8环烷胺基、芳基或杂芳基。 R 5 is independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkane Group, cycloalkyl group, nitro group, cyano group, amino group; wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group and cycloalkyl group are each independently covered by 0-5 R a substituent; R & lt optionally a from: C1 ~ C6 alkyl, halogen, hydroxy, C1 ~ C6 heteroalkyl, C1 ~ C6 alkoxy group, C1 ~ C6 alkyl group, a cycloalkyl group, heterocycloalkyl or cyano Group; Ring Q2 is optional from: five-membered, six-membered or seven-membered saturated, unsaturated, aromatic, heteroaromatic, spiro or bridged ring, and may contain 0 to 3 heteroatoms, any heteroatom Any hydrogen atom selected from N, O, S, ring Q2 can be substituted by the following substituents: deuterium, hydroxyl, halogen, cyano, ester, amide, ketone carbonyl, amino, C1-C6 alkyl, C1- C6 haloalkyl, C1～C6 thioalkyl, C1～C6 alkoxy, C1～C6 heteroalkyl, C1～C6 alkylamino, C3～C6 cycloalkyl, C3～C8 cycloalkylamino, aryl Or heteroaryl.
  9. 如权利要求1或2所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，所述化合物可以任选自以下结构所示的化合物：The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the compound may be selected from the compounds represented by the following structure:
    Figure PCTCN2020091425-appb-100028
    Figure PCTCN2020091425-appb-100028
    Figure PCTCN2020091425-appb-100029
    Figure PCTCN2020091425-appb-100029
    Figure PCTCN2020091425-appb-100030
    Figure PCTCN2020091425-appb-100030
    Figure PCTCN2020091425-appb-100031
    Figure PCTCN2020091425-appb-100031
    Figure PCTCN2020091425-appb-100032
    Figure PCTCN2020091425-appb-100032
  10. 权利要求1或2所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，药学上可接受的盐为无机酸盐或有机酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, and the inorganic The acid salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; the organic acid salt is selected from formate, acetate , Trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citric acid Salt, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
  11. 一种药物组合物，其含有治疗有效量的如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，以及药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable Carrier.
  12. 一种如权利要求1所述的式I'化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于RET激酶抑制剂药物方面的应用。An application of the compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in the preparation of a RET kinase inhibitor drug.
  13. 一种如权利要求1所述的式I'的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于调节RET激酶活性或治疗RET相关疾病药物方面的应用。A compound of formula I'according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is useful in the preparation of a drug for regulating RET kinase activity or treating RET-related diseases application.
  14. 权利要求13所述的用途，其特征在于，所述的RET相关疾病包括癌症。The use according to claim 13, wherein the RET-related diseases include cancer.
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AU2020280699A1 (en) 2022-01-27
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